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问AI · 口服难的PROTAC药物怎样突破成药瓶颈？摘要靶向蛋白降解（TPD）技术作为药物研发领域的革命性突破，通过利用细胞内源性降解机制清除致病蛋白，为传统小分子抑制剂难以成药的靶点提供了全新治疗策略。近年来，PROTAC、分子胶、LYTAC等TPD技术快速发展，但靶点选择的系统性和全面性仍是制约该领域临床转化的关键瓶颈。本综述系统整理了216个TPD领域的热门靶点，涵盖激酶与信号蛋白、核受体与转录因子、表观遗传与染色质调控因子、凋亡与细胞周期蛋白、神经变性疾病靶点、病毒蛋白靶点及其他酶与杂项靶点七大类别。文章深入分析了每个靶点的生物学功能及其在疾病发生发展中的作用机制，并系统总结了基于各类TPD技术的新药管线进展。通过对这些靶点的全面梳理，旨在为TPD药物研发提供系统性的靶点选择依据和技术参考，推动该领域从靶点发现向临床应用的转化。关键词靶向蛋白降解；PROTAC；分子胶；激酶；表观遗传；转录因子；新药管线前言靶向蛋白降解（Targeted Protein Degradation, TPD）技术作为近年来生物医药领域的一项革命性突破，正逐步重塑传统药物研发的范式。与依赖“占据驱动”模式、需与靶蛋白活性位点结合的传统小分子抑制剂不同，TPD技术通过劫持细胞内的固有蛋白清除机制，实现对致病蛋白的特异性、催化性降解[1]。这一策略的核心在于利用细胞内两大主要降解系统：泛素-蛋白酶体系统（UPS）和溶酶体途径。其中，蛋白水解靶向嵌合体（PROTAC）作为TPD领域研究最为深入的技术，通过一个双功能分子同时招募靶蛋白（POI）和E3泛素连接酶，形成三元复合物，进而诱导靶蛋白泛素化并被26S蛋白酶体识别并降解[2]。这种事件驱动的机制赋予了PROTAC诸多传统抑制剂无法比拟的优势，包括能够靶向传统意义上的“不可成药”靶点（如转录因子、支架蛋白）、在亚化学计量浓度下发挥作用、以及有效克服因靶点突变或代偿性信号通路激活导致的耐药性[3][4]。除了PROTAC，TPD技术家族还包括分子胶、溶酶体靶向嵌合体（LYTAC）、自噬靶向嵌合体（AUTAC）等多种策略，它们分别利用不同的降解途径，极大地拓展了可降解靶蛋白的范畴，从胞内蛋白延伸至膜蛋白和胞外蛋白[5][6]。TPD技术的迅猛发展，尤其为攻克那些长期被视为“不可成药”的靶点带来了曙光。激酶、表观遗传调控因子和转录因子等蛋白家族，因其在肿瘤发生发展中的核心驱动作用，成为TPD技术应用的热点领域。例如，针对表皮生长因子受体（EGFR）这一在非小细胞肺癌（NSCLC）中至关重要的驱动基因，传统酪氨酸激酶抑制剂（TKI）虽取得显著疗效，但获得性耐药（如T790M、C797S突变）问题日益突出[7]。PROTAC技术通过降解整个EGFR蛋白，而非仅仅抑制其激酶活性，为克服这些耐药突变提供了全新思路。研究表明，基于VHL或CRBN E3连接酶的PROTAC分子能够有效降解包括EGFR Del19、L858R/T790M乃至三重突变体在内的多种EGFR突变蛋白，展现出优于传统抑制剂的抗增殖活性和更持久的信号通路抑制效果[8][9][10]。同样，对于雄激素受体（AR）和溴结构域蛋白4（BRD4）等关键靶点，已有多个基于PROTAC技术的化合物，如靶向AR的ARV-110和靶向ER的ARV-471，成功进入临床试验阶段，验证了TPD技术在实体瘤治疗中的巨大潜力[11][12]。这些进展表明，TPD技术正逐步将“不可成药”的愿景变为现实。TPD技术的核心在于对E3泛素连接酶的有效招募。目前，绝大多数PROTAC分子依赖于少数几种经过充分验证的E3连接酶，其中以Cereblon（CRBN）和Von Hippel-Lindau（VHL）最为常见[13][14]。CRBN和VHL因其高效的降解活性和成熟的配体化学，成为PROTAC设计的首选“引擎”。然而，过度依赖这两种连接酶也带来了局限性，例如，在某些肿瘤细胞中，CRBN或VHL的表达水平可能较低或存在功能缺失，从而导致PROTAC耐药[15][16]。为克服这一瓶颈，研究者们正积极拓展E3连接酶的工具箱，探索利用MDM2、IAP、DCAF1、RNF114、GID4等新型E3连接酶[17][18][19][15]。例如，基于DCAF1的PROTAC已被证明能够有效降解BTK等靶点，并在对CRBN-PROTAC耐药的细胞中仍保持活性[16]。此外，通过设计双E3连接酶招募的PROTAC分子，如同时招募CRBN和VHL的异源三价PROTAC，可以协同增强降解效率，并可能延缓耐药性的产生[20][21]。这些努力不仅丰富了TPD技术的应用场景，也为实现组织特异性降解和克服耐药提供了新的策略。综上所述，TPD技术已从概念验证阶段迈入快速发展的临床应用转化期。通过对216个已验证或高潜力的TPD靶点进行系统分析，我们可以清晰地看到，该技术的靶点谱系正以前所未有的速度扩展，覆盖了激酶、表观遗传因子、转录因子、核受体等多个关键蛋白类别。随着新型E3连接酶配体的不断发现、PROTAC分子设计的日益精进（如连接子优化、光控激活、靶向递送等）[22][23][24]，以及分子胶等新兴降解模式的涌现[25]，TPD技术有望在未来覆盖更多与疾病相关的蛋白，为肿瘤、神经退行性疾病、自身免疫性疾病等多种重大疾病的治疗提供全新的、高效的解决方案[5][26]。本综述旨在基于对现有文献和靶点数据的深入分析，系统梳理TPD领域的关键靶点、降解策略及新药研发管线，为研究者提供一份全面的靶点图谱和研发参考。1. 激酶与信号蛋白靶点1.1 酪氨酸激酶类靶点酪氨酸激酶（Tyrosine Kinases, TKs）在细胞信号转导中扮演核心角色，其异常激活与多种恶性肿瘤的发生、发展及耐药密切相关。靶向蛋白降解（TPD）技术，特别是蛋白水解靶向嵌合体（PROTACs），为克服传统小分子激酶抑制剂（TKIs）的局限性提供了革命性策略。PROTACs通过同时结合靶蛋白和E3泛素连接酶，诱导靶蛋白泛素化并被蛋白酶体降解，从而彻底消除其激酶活性和非催化支架功能[27][28]。这一机制在应对由靶点突变、扩增或代偿通路激活引起的耐药性方面展现出显著优势[29]。在众多酪氨酸激酶靶点中，ABL1/ABL2（Abl家族激酶）是TPD策略的典型成功案例。在慢性髓系白血病（CML）中，BCR-ABL融合蛋白的持续激活是核心致病机制。尽管第一代TKI伊马替尼取得了巨大成功，但耐药突变（尤其是T315I）的出现严重限制了其长期疗效[30]。PROTAC降解剂能够通过泛素-蛋白酶体途径完全消除BCR-ABL蛋白，不仅抑制其激酶活性，还消除了其作为信号支架的非催化功能，从而在克服耐药性方面优于传统TKI[30]。例如，化合物SJ3140等已在临床前模型中展示出对包括T315I突变在内的多种耐药突变体的高效降解活性和抗肿瘤效果[28]。此外，针对ALK（间变性淋巴瘤激酶）的PROTAC降解剂也取得了重要进展。ALK融合突变是非小细胞肺癌和神经母细胞瘤的关键驱动因素，而传统TKI治疗后常出现G1202R等耐药突变。PROTAC分子如C4-1能够有效降解ALK蛋白，包括这些耐药突变体，并在临床前模型中显示出显著的抗肿瘤活性，为克服ALK-TKI耐药提供了新途径[28]。BTK（布鲁顿酪氨酸激酶）是B细胞恶性肿瘤中的关键治疗靶点。共价BTK抑制剂（如伊布替尼）虽有效，但C481S等突变导致的获得性耐药是临床难题[31]。PROTAC技术通过诱导BTK蛋白的完全降解，能够有效清除野生型及C481S突变型BTK，从根本上解决耐药问题[32]。临床候选药物如MT-802和NX-2127已进入临床试验，展现出强大的BTK降解能力和抗肿瘤活性[32][33]。此外，针对CSF1R（集落刺激因子1受体）的PROTAC降解剂则代表了TPD在肿瘤微环境调控中的应用。CSF1R在肿瘤相关巨噬细胞（TAMs）中高表达，是维持免疫抑制性微环境的关键。通过PROTAC降解CSF1R，可重编程TAMs，使其从促肿瘤表型向抗肿瘤表型转化，从而激活抗肿瘤免疫。在乳腺癌模型中，CSF1R降解剂已显示出免疫激活效应和抑制肿瘤生长的潜力，目前处于临床前研究阶段[28]。最后，AAK1（AP2相关激酶1）作为参与内吞作用和受体运输调控的激酶，其促肿瘤侵袭功能也成为了TPD策略的潜在靶点，尽管目前相关研究仍处于早期发现阶段，但为拓展TPD的应用范围提供了新思路[28]。综上所述，TPD技术通过降解而非抑制酪氨酸激酶，为克服耐药、消除支架功能以及调控肿瘤微环境提供了强大工具，正引领着靶向治疗的新方向。1.2 丝氨酸/苏氨酸激酶类靶点丝氨酸/苏氨酸激酶（STKs）是蛋白激酶超家族中最大的分支之一，在调控细胞生长、增殖、代谢和凋亡等关键信号通路中扮演核心角色。与酪氨酸激酶（TKs）相比，STKs在进化上呈现出独特的构象景观，其激活环倾向于采取更稳定的“DFG-out”折叠构象，这导致它们对II型抑制剂的结合亲和力通常弱于TKs[34][35]。这种构象差异源于激活环和催化环中残基替换的积累，使得STKs在信号转导中具有不同的调控模式[36]。在肿瘤治疗领域，STKs已成为重要的药物靶点，而蛋白水解靶向嵌合体（PROTAC）技术作为一种新兴策略，通过诱导靶蛋白的泛素化降解，能够同时抑制STKs的激酶活性和非催化功能（如脚手架功能），从而克服传统小分子抑制剂的局限性[37]。在PI3K/AKT/mTOR通路中，AKT1/2/3（蛋白激酶B）是核心节点，其异常激活常见于PTEN缺失的肿瘤中。PROTAC降解剂如MS21不仅能有效抑制AKT的激酶活性，还能消除其作为信号平台组装其他蛋白的脚手架功能，从而在PTEN缺失的肿瘤模型中展现出比传统抑制剂更强的抗肿瘤活性。这种双重作用机制为治疗这类难治性肿瘤提供了新的思路。BRAF（B-Raf激酶）是RAS-RAF-MEK-ERK通路的关键成员，其V600E突变在黑色素瘤中高频出现。传统BRAF抑制剂如达拉非尼虽有效，但常因MEK的反馈性激活而导致耐药。PROTAC降解剂如SJF-0628通过完全消除BRAF蛋白，阻断了其作为支架蛋白重新激活下游信号的能力，从而有效克服了这种耐药机制，并显示出良好的降解活性和选择性[38]。CDK4/5/6（周期蛋白依赖性激酶4/5/6）在细胞周期G1/S转换中起关键作用，是乳腺癌等癌症的重要治疗靶点。现有的CDK4/6抑制剂通过竞争性结合ATP位点来抑制激酶活性，但肿瘤细胞可通过多种机制产生耐药。PROTAC降解剂通过诱导CDK蛋白的持续降解，实现了对RB通路的更持久抑制，并能克服由CDK6扩增或p16缺失引起的耐药。化合物如PF-06873600已进入早期临床试验，显示出优于传统抑制剂的潜力。MEK1/2（丝裂原活化蛋白激酶激酶）位于RAS-RAF-MEK-ERK通路的核心，传统MEK抑制剂常因上游RAS或RAF的反馈激活而疗效受限。PROTAC降解剂通过彻底清除MEK蛋白，绕过了这一反馈机制，在KRAS突变型肿瘤中显示出显著疗效，目前正处于临床前验证阶段[39]。PLK1/2/3/4（Polo样激酶）家族成员在有丝分裂调控中发挥不同作用。广谱PLK抑制剂因同时抑制多个家族成员而带来严重毒性。PLK1特异性PROTAC降解剂通过选择性降解PLK1，保留了PLK2/3/4的正常功能，从而在耐药性白血病模型中展现出更宽的治疗窗口。多个PROTAC分子已在动物模型中验证了其抗肿瘤活性和安全性。此外，STK33在食管鳞状细胞癌中过表达，并通过炎症相关通路促进肿瘤增殖和转移，沉默其表达可抑制肿瘤生长，提示其作为治疗靶点的潜力[40]。在细菌领域，STKs同样调控着细胞壁稳态、毒力和耐药性，如金黄色葡萄球菌的Stk和艰难梭菌的PrkC，它们通过磷酸化底物蛋白（如FemX、CwlA）来调节细胞壁合成和水解，这为开发新型抗菌药物提供了潜在靶点[41][42][43]。1.3 免疫相关激酶靶点JAK1/JAK2/JAK3/TYK2作为Janus激酶家族的核心成员，是JAK-STAT信号通路的关键启动子。该通路介导多种细胞因子和生长因子的信号转导，在免疫调节、炎症反应及造血过程中发挥不可替代的作用。传统的小分子激酶抑制剂虽能有效阻断JAK的催化活性，但往往难以完全抑制其非催化功能，且长期使用易产生耐药性。蛋白水解靶向嵌合体（PROTAC）技术的出现为克服这些局限提供了新策略。通过设计双功能分子同时结合JAK激酶和E3泛素连接酶，PROTAC能够诱导JAK蛋白的泛素化并随后被蛋白酶体降解，从而实现对该信号节点的彻底清除。这种降解模式不仅能消除激酶的催化活性，还能破坏其作为支架蛋白参与的信号复合物组装，理论上可实现对多种细胞因子信号的同步抑制。例如，已有针对JAK2的PROTAC降解剂如JQ-1-JAK2进入临床前研究阶段，显示出在骨髓增殖性肿瘤和自身免疫病中的巨大潜力。此外，鉴于JAK家族成员在多种自身免疫性疾病（如类风湿性关节炎、银屑病）中的关键作用，开发能够选择性降解特定JAK亚型或同时靶向多个JAK成员的PROTAC分子，有望提供更精准、更持久的治疗效果，并可能降低传统抑制剂带来的全身性免疫抑制风险。MAP4K1/3/5（丝裂原活化蛋白激酶激酶激酶激酶）属于Ste20样丝氨酸/苏氨酸激酶家族，在免疫细胞信号转导中扮演着复杂的调控角色。其中，MAP4K1（又称HPK1）被鉴定为T细胞受体（TCR）和B细胞受体（BCR）信号的负调控因子，其通过磷酸化并诱导SLP-76和BLNK等关键适配蛋白的泛素化降解，从而抑制免疫突触的形成和下游信号级联反应[44]。研究表明，HPK1的缺失或功能丧失可增强T细胞的细胞因子分泌、病毒清除和肿瘤生长抑制能力，使其成为肿瘤免疫治疗中极具吸引力的靶点[45][46]。然而，由于HPK1与MAP4K家族其他成员（如MAP4K3/GLK）在激酶结构域上具有高度序列同源性，开发高选择性的小分子抑制剂面临巨大挑战。值得注意的是，HPK1的非催化支架功能也被认为在肿瘤免疫调节中发挥作用，这进一步增加了传统抑制策略的复杂性[47]。PROTAC技术通过诱导HPK1蛋白的完全降解，能够同时消除其催化功能和支架功能，展现出独特的优势。已有研究团队开发出口服有效的HPK1 PROTAC分子，在术后肿瘤模型中，该降解剂能够有效下调嵌合抗原受体T细胞（CAR-T）中的HPK1水平，促进其对实体瘤复发的抑制效率，并在联合抗PD-L1抗体治疗中显著增强肿瘤内CD45⁺免疫细胞和CD3⁺ T细胞的浸润[48]。这些发现表明，靶向HPK1的PROTAC策略在增强抗肿瘤免疫方面具有巨大的转化潜力。RIPK1/RIPK2/RIPK3（受体相互作用蛋白激酶）是调控细胞命运和炎症反应的关键分子。RIPK1作为细胞应激的“哨兵”，其激酶活性可触发细胞凋亡和坏死性凋亡，而其非催化的支架功能则介导强大的促生存信号，癌细胞常劫持此功能以逃避免疫监视[49]。RIPK2则是NOD1/2信号通路的核心适配蛋白，在固有免疫应答中通过激活NF-κB通路调控促炎细胞因子的产生，其异常激活与炎症性肠病等自身免疫性疾病密切相关[50]。PROTAC介导的RIPK2降解已在体内外展现出显著优势，例如，化合物GSK’481的衍生物能够在大鼠体内以低剂量实现内源性RIPK2的持久降解，其药效学效应远超药物的药代动力学存在时间，这种PK/PD分离特性为低剂量、低频次给药方案提供了可能[51]。对于RIPK1，PROTAC降解剂LD4172的研发揭示了其独特的治疗潜力。LD4172不仅能有效降解RIPK1，还能通过解除其支架功能，同时增强NF-κB、MAPK和IFN信号输出，并促进RIPK3激活和坏死性凋亡的诱导，从而触发免疫原性细胞死亡（ICD），增强肿瘤对放疗和免疫检查点抑制剂的敏感性[52][49]。这些研究共同表明，通过PROTAC技术降解RIPK家族成员，能够同时干预其激酶依赖和支架依赖的功能，为治疗炎症性疾病和克服肿瘤免疫治疗耐药性提供了强有力的新工具。TBK1（TANK结合激酶1）是连接先天免疫和自噬过程的关键信号枢纽。在病毒感染时，TBK1被模式识别受体（如RIG-I样受体）激活，通过磷酸化IRF3/7转录因子，诱导I型干扰素（IFN-I）和促炎细胞因子的产生，这是宿主抗病毒防御的核心环节[53]。然而，TBK1的过度或持续激活会导致IFN-I的过量产生，从而引发自身免疫性疾病。此外，TBK1还参与自噬的调控，通过磷酸化自噬受体（如p62）来促进对胞内病原体和受损细胞器的清除[54]。TBK1的激酶活性和支架功能在信号传导中均至关重要。传统的小分子抑制剂主要靶向其ATP结合位点以抑制激酶活性，但无法破坏其作为支架蛋白参与的信号复合物（如与STING、IRF3的相互作用）的组装。PROTAC技术通过诱导TBK1蛋白的完全降解，能够同时消除其催化功能和支架功能，理论上可实现对TBK1信号通路的更彻底阻断。值得注意的是，MAP4K1被鉴定为TBK1的负调控因子，它通过招募E3泛素连接酶DTX4，促进TBK1/IKKε的K48连接泛素化，进而介导其蛋白酶体降解[53]。这一内源性调控机制的发现，为设计靶向TBK1的PROTAC分子提供了重要的生物学基础。目前，针对TBK1的PROTAC降解剂开发仍处于靶点验证阶段，但鉴于其在自身免疫病（如系统性红斑狼疮）和炎症性疾病中的治疗潜力，该领域的研究正日益受到关注。ZAP70（ζ链相关蛋白激酶70）是T细胞受体（TCR）信号通路中不可或缺的酪氨酸激酶。在T细胞活化过程中，TCR与抗原肽-MHC复合物结合后，Src家族激酶（如Lck）磷酸化TCR的CD3链和ζ链上的免疫受体酪氨酸激活基序（ITAM），随后ZAP70通过其SH2结构域与磷酸化的ITAM结合并被激活。活化的ZAP70进而磷酸化下游适配蛋白（如LAT和SLP-76），启动一系列信号级联反应，最终导致T细胞增殖、分化和细胞因子产生[55]。ZAP70的功能异常与多种自身免疫性疾病密切相关，例如，在系统性红斑狼疮（SLE）患者中，ZAP70的表达和活性异常可导致T细胞信号失衡，促进自身反应性T细胞的活化和自身抗体的产生。此外，ZAP70在慢性淋巴细胞白血病（CLL）中作为预后标志物，其高表达与疾病侵袭性相关。鉴于ZAP70在T细胞免疫中的核心地位，开发能够精确调控其活性的治疗策略具有重要意义。PROTAC技术为靶向ZAP70提供了新的思路。通过设计能够同时结合ZAP70和E3泛素连接酶的双功能分子，可以诱导ZAP70蛋白的特异性降解，从而在蛋白水平上彻底消除其功能。这种策略的优势在于，它不仅能抑制ZAP70的激酶活性，还能破坏其作为信号平台组装所依赖的支架功能。已有研究报道，PROTAC分子在动物模型中显示出可逆转SLE疾病进展的潜力，这为开发针对自身免疫病的ZAP70降解剂提供了令人鼓舞的临床前证据。未来，通过优化PROTAC分子的药代动力学特性和选择性，有望开发出能够精准调控T细胞免疫、治疗自身免疫性疾病的新型治疗药物。1.4 其他信号蛋白靶点KEAP1（Kelch样ECH相关蛋白1）是NRF2的关键负调控因子，在维持细胞氧化还原稳态中发挥核心作用。靶向蛋白降解（TPD）技术通过降解KEAP1，能够稳定并激活NRF2，从而发挥抗炎和细胞保护作用，在神经退行性疾病中展现出巨大潜力。研究表明，KEAP1的降解可解除其对NRF2的抑制，促进下游抗氧化基因的表达，有效减轻氧化应激损伤[56]。已有研究团队设计了针对KEAP1的PROTAC分子，并在帕金森病模型中验证了其通过稳定NRF2来保护多巴胺能神经元的有效性[57]。这种策略的优势在于，通过“事件驱动”的药理学模式，能够催化性地降解KEAP1，实现对NRF2信号的持续激活，相较于传统的小分子抑制剂，具有更高的效率和更低的耐药性风险[58]。此外，KEAP1作为E3连接酶的底物适配器，其降解本身也拓展了TPD技术在调控细胞内信号网络中的应用范围[59]。STING（干扰素基因刺激因子）是连接先天免疫与适应性免疫的关键接头蛋白，在抗病毒免疫中不可或缺。然而，STING的过度激活会导致自身炎症性疾病，如STING相关婴儿期早发性血管病（SAVI）。因此，精准调控STING信号成为治疗自身免疫病和炎症性疾病的重要策略。TPD技术通过设计STING降解剂，能够精确地降低STING蛋白水平，从而抑制其过度激活引起的炎症级联反应[60]。目前，针对STING的降解剂研究仍处于早期发现阶段，但已有概念验证性研究展示了其可行性。例如，利用PROTAC技术将STING招募至E3连接酶，实现其泛素化降解，从而在细胞模型中有效抑制了STING依赖的炎症因子产生[61]。这种策略的优势在于能够完全消除STING的蛋白功能，包括其非依赖配体的支架功能，为治疗STING相关疾病提供了全新的干预手段[62]。CBL-B（Cbl原癌基因B）是一种E3泛素连接酶，在T细胞活化中扮演负调控角色。CBL-B通过泛素化降解T细胞受体（TCR）信号通路中的关键分子，如ZAP70和PKCθ，从而抑制T细胞的激活和抗肿瘤免疫应答。因此，降解CBL-B被认为是增强抗肿瘤免疫的有效策略。研究表明，通过小分子降解剂靶向CBL-B，能够解除其对T细胞活化的抑制，增强T细胞的增殖、细胞因子分泌和杀伤功能[60]。这种策略与免疫检查点抑制剂（如PD-1/PD-L1抗体）联用，具有巨大的协同潜力，有望克服肿瘤免疫逃逸，提高免疫治疗的响应率[63]。目前，已有多个小分子CBL-B降解剂处于临床前研究阶段，并展示了显著的免疫激活效应，为开发新型肿瘤免疫疗法提供了有力工具[64]。VAV1（Vav鸟苷酸交换因子1）是Rho家族GTP酶（如Rac1、RhoA）的鸟苷酸交换因子，在T细胞和B细胞受体信号传导中促进肌动蛋白细胞骨架重塑，对淋巴细胞的活化、增殖和迁移至关重要。VAV1的异常激活与多种血液系统恶性肿瘤，特别是T细胞急性淋巴细胞白血病（T-ALL）的发生发展密切相关。因此，靶向降解VAV1成为治疗T-ALL的潜在策略。通过设计PROTAC分子，可以特异性地将VAV1招募至E3连接酶，诱导其泛素化降解，从而阻断下游致癌信号通路[65]。尽管目前尚无公开的针对VAV1的临床管线，但多个研究团队已开始进行PROTAC的设计与优化，旨在开发出高效、特异的VAV1降解剂[66]。这些研究有望为T-ALL等VAV1驱动的血液肿瘤提供新的治疗选择，并进一步拓展TPD技术在信号蛋白靶点中的应用[67]。2. 核受体与转录因子靶点2.1 核激素受体靶点核激素受体（Nuclear Hormone Receptors, NHRs）作为配体激活的转录因子，在细胞增殖、分化及代谢调控中发挥核心作用，其异常表达或突变是多种癌症发生及耐药的关键驱动因素。靶向蛋白降解（TPD）技术，特别是PROTACs，通过劫持泛素-蛋白酶体系统实现对NHRs的催化性降解，为克服传统小分子抑制剂的耐药性提供了革命性策略[68]。在前列腺癌领域，雄激素受体（AR）的持续活化是疾病进展的核心，而AR剪接变体（如AR-V7）的表达导致对恩杂鲁胺等药物的耐药。PROTAC分子ARV-110（bavdegalutamide）和ARV-766通过同时降解全长AR和AR-V7变体，已在II期临床试验中展现出克服耐药性的潜力，解决了传统疗法因AR信号通路再激活而失效的临床难题[68]。此外，针对AR蛋白稳定性的研究揭示了核转出信号（NESAR）通过泛素-蛋白酶体途径介导AR降解的机制，为开发新型AR降解策略提供了分子基础[69]。在乳腺癌中，雌激素受体α（ERα）的ESR1突变是导致内分泌治疗耐药的主要原因。PROTAC分子ARV-471（vepdegestrant）通过靶向降解ERα蛋白，在I/II期临床试验中展示了良好的安全性和药效，尤其对ESR1突变型乳腺癌患者表现出显著疗效[68]。这一策略有效规避了因配体结合域突变导致的传统选择性ER下调剂（SERD）耐药问题。孕激素受体（PR）在子宫内膜癌和乳腺癌中高表达，传统激素治疗常因PR信号通路的代偿性激活而受限。临床前研究表明，基于PROTAC的PR降解剂在PR阳性子宫内膜癌模型中展现出优于孕激素的治疗效果，通过彻底清除PR蛋白而非单纯抑制其活性，为激素难治性肿瘤提供了新选择[68]。视黄酸受体α（RARα）在急性早幼粒细胞白血病（APL）中因PML-RARα融合蛋白的形成而驱动疾病，全反式维甲酸（ATRA）虽能诱导分化，但耐药性普遍存在。PROTAC降解剂通过靶向PML-RARα融合蛋白，在动物模型中成功克服了ATRA耐药，并恢复了分化诱导的敏感性[68]。糖皮质激素受体（GR）在炎症和血液肿瘤中发挥关键作用，但传统糖皮质激素的系统性副作用限制了其临床应用。PROTAC分子通过选择性降解GR蛋白，在急性淋巴细胞白血病模型中展示了治疗优势，同时避免了长期激素治疗带来的代谢紊乱和免疫抑制等副作用[68]。此外，针对肝X受体（LXR）的PROTAC开发也取得了进展，GW3965-PEG5-VH032等分子通过VHL E3连接酶依赖的途径有效降解LXRβ蛋白，为治疗LXR相关代谢性疾病提供了新工具[70]。这些进展表明，PROTAC技术通过靶向NHRs的蛋白水平而非活性，为克服传统激素治疗的耐药性和副作用开辟了全新路径。2.2 转录调控因子靶点转录调控因子在细胞命运决定和疾病发生中扮演核心角色，其异常表达或功能失调是多种肿瘤和免疫疾病的驱动因素。靶向蛋白降解（TPD）技术，特别是分子胶和PROTACs，为干预这些传统上难以成药的转录因子提供了革命性策略。Ikaros（IKZF1）、Helios（IKZF2）和Aiolos（IKZF3）是锌指转录因子，在淋巴细胞发育和恶性转化中起关键作用。经典的分子胶如来那度胺通过招募CRBN-CRL4 E3泛素连接酶，特异性地诱导IKZF1和IKZF3的泛素化降解，从而在多发性骨髓瘤中发挥治疗作用。针对IKZF2的新一代分子胶如iBERIDANEN正在开发中，旨在用于自身免疫病的治疗，多个相关管线已进入临床试验阶段。FOXP3作为调节性T细胞（Treg）的主转录因子，其降解能够有效增强抗肿瘤免疫力，在肿瘤免疫治疗中展现出巨大潜力。然而，开发具有高度特异性的FOXP3降解剂仍面临挑战，目前该靶点主要处于靶点验证阶段。STAT3在多种肿瘤中被异常激活，其PROTAC降解剂如SD-36能够高效地降解STAT3蛋白，克服其作为转录因子和信号转导子的双重功能，在血液肿瘤和实体瘤模型中均显示出广泛的抗肿瘤活性，已在动物模型中验证了其有效性。STAT5和STAT6同样在肿瘤发生和免疫调节中至关重要，针对STAT5的降解剂主要用于血液肿瘤，而STAT6降解剂则被探索用于Th2型炎症性疾病，目前两者均处于临床前研究阶段。c-Myc作为原癌基因转录因子，因其缺乏明确的活性位点而传统上被认为无法成药。PROTAC技术通过招募E3连接酶实现了对c-Myc的瞬时降解，在多种肿瘤模型中展现出抗肿瘤活性，已有如MYC-specific PROTAC等分子在临床前验证中取得进展。BCL6在弥漫大B细胞淋巴瘤中作为转录抑制因子，其PROTAC降解剂能够重新激活BCL6的靶基因，在动物模型中引起肿瘤消退，已有多个PROTAC分子处于临床前开发阶段。SALL4是胚胎发育相关的转录因子，在肝癌和白血病中异常表达，其降解剂有望用于靶向这类癌症干细胞，目前仍处于靶点验证的早期阶段。这些转录调控因子靶点的成功开发，标志着TPD技术在攻克“不可成药”靶点方面迈出了关键一步，为肿瘤和免疫疾病的治疗开辟了新的途径。3.表观遗传与染色质调控因子靶点3.1 溴结构域蛋白（BET）靶点溴结构域和末端外结构域（BET）蛋白家族，包括BRD2、BRD3、BRD4、BRDT以及BRD7和BRD9等，是一类关键的“表观遗传阅读器”，通过特异性识别组蛋白上的乙酰化赖氨酸残基来调控基因转录[71][72]。其中，BRD4是蛋白靶向降解（TPD）领域最经典且研究最为深入的靶点之一。基于PROTAC（蛋白水解靶向嵌合体）技术的分子，如MZ1、ARV-825和dBET1等，能够高效且选择性地诱导BRD4降解。例如，MZ1通过将JQ1（BET抑制剂）与VHL E3连接酶配体连接，实现了对BRD4的优先降解，而对BRD2和BRD3的作用较弱，这种选择性源于其诱导形成的三元复合物的独特构象[73]。ARV-825在小细胞肺癌（SCLC）中展现出卓越的抗增殖活性，通过靶向BRD4来抑制MYC癌基因的转录，为SCLC的联合化疗提供了有价值的辅助手段[74]。此外，dBET6和MZ1等PROTAC分子在降解BRD4时表现出“蛋白年龄偏好性”，即优先降解预先存在的BRD4蛋白，而对新合成的BRD4降解效率较低，这揭示了蛋白质稳态动态平衡在TPD疗效中的关键作用[75]。这些PROTAC分子在多种血液肿瘤和实体瘤中均展现出强效的抗肿瘤活性，部分化合物如ARV-825已进入I期临床试验阶段[72][76]。值得注意的是，一些PROTAC分子同时覆盖BRD2、BRD3和BRD4，如化合物15，它能有效降解BRD4和BRD2，并在急性白血病和实体瘤细胞系中表现出强效的细胞生长抑制活性[77]。此外，新型的酶诱导超分子PROTAC（eiSupTACs）通过利用肿瘤特异性生物化学和生物正交化学，实现了对BRD4的肿瘤靶向选择性降解，在多种癌细胞系中展现出高效且特异的降解活性，为精准治疗提供了新策略[78]。除了经典的BRD2/3/4，BRD7和BRD9在染色质重塑复合物中扮演着特定角色，并已成为新兴的治疗靶点。BRD9是滑膜肉瘤中的一个关键致癌因子，其降解剂如VZ185等PROTAC分子在临床前研究中已显示出良好的选择性，能够有效抑制滑膜肉瘤细胞的增殖[72]。这些降解剂通过劫持E3泛素连接酶，特异性地将BRD9标记并降解，从而干扰SWI/SNF染色质重塑复合物的功能，为治疗这类罕见肿瘤提供了新的思路[79]。此外，CECR2（猫眼综合征染色质重塑因子）与神经发育和肿瘤发生相关，其降解剂能够干预特定的染色质状态，目前仍处于早期发现阶段。尽管针对CECR2的PROTAC分子尚未进入临床，但这一方向拓展了BET家族蛋白降解的应用范围，有望为相关疾病提供新的治疗策略。总体而言，BET蛋白家族，尤其是BRD4，已成为TPD领域最成功的靶点之一，其降解剂在临床前和临床研究中均展现出巨大的治疗潜力，同时针对BRD7、BRD9等非经典BET成员的降解剂也在不断涌现，丰富了该领域的治疗策略[72][80]。3.2 组蛋白甲基转移酶靶点组蛋白甲基转移酶（HMTs）通过催化组蛋白赖氨酸或精氨酸残基的甲基化，在基因表达调控、染色质结构维持及细胞命运决定中发挥核心作用[81][82]。其功能异常与多种肿瘤的发生发展密切相关，因此成为靶向蛋白降解（TPD）策略的重要应用领域[82][83]。EZH2是PRC2复合物的催化亚基，负责催化H3K27me3修饰，在弥漫大B细胞淋巴瘤中因Y641突变而异常活化[84]。与传统的酶活性抑制剂（如他泽司他）不同，PROTAC降解剂能够同时去除EZH2的酶活性和支架功能，从而更彻底地抑制其致癌作用[85]。已有研究报道了基于VHL的EZH2降解剂P4，该分子能有效诱导乳腺癌细胞中EZH2蛋白降解，并显著降低H3K27me3水平，诱导细胞凋亡和G0/G1期阻滞[85]。此外，靶向EED的PROTAC分子通过降解PRC2复合体的核心支架蛋白，可同时抑制EZH1和EZH2的活性，在EZH2突变型肿瘤中展现出强效的抗肿瘤活性[83]。WDR5是MLL复合体组装的关键组分，参与H3K4甲基化的调控，其降解剂在MLL重排型白血病中具有潜在治疗价值，目前仍处于临床前研究阶段[86]。PRMT5催化对称性二甲基精氨酸修饰，在多种肿瘤中作为合成致死靶点，尤其适用于MTAP缺失型肿瘤[82]。目前已有多个PRMT5的PROTAC降解剂处于临床前开发阶段，旨在克服传统抑制剂的耐药性问题[82]。CARM1（PRMT4）在乳腺癌和前列腺癌中作为转录共激活因子发挥作用，其降解剂有望替代传统抑制剂，目前正处于靶点验证阶段[87]。此外，NSD2作为催化H3K36me2的甲基转移酶，在多种血液肿瘤中因突变或融合事件而异常激活[88]。近期研究通过DNA编码文库筛选发现了靶向NSD2 PWWP1结构域的小分子配体，并成功将其转化为VHL招募的PROTAC降解剂，该分子能有效降低H3K36me2水平并抑制细胞增殖[88]。另一项研究则利用FBXO22 E3连接酶开发了新型NSD2降解剂UNC8732，该分子通过代谢激活的醛基共价结合FBXO22的C326位点，在急性淋巴细胞白血病细胞中诱导生长抑制和凋亡[89][90]。这些研究共同揭示了HMTs作为PROTAC靶点的巨大潜力，为开发新型抗肿瘤药物提供了重要方向。3.3 组蛋白去乙酰化酶（HDAC）与去甲基化酶靶点组蛋白去乙酰化酶（HDAC）和组蛋白去甲基化酶是表观遗传调控网络中的关键酶类，它们通过移除组蛋白上的乙酰基或甲基基团，共同参与染色质结构的重塑和基因表达的精密调控。在多种肿瘤及神经退行性疾病中，这些酶的异常表达或活性失调是驱动疾病进展的重要因素。因此，靶向这些酶类的蛋白降解技术，如PROTACs，为开发新型治疗策略提供了极具潜力的方向。HDAC家族成员众多，其中HDAC6因其独特的底物特异性而备受关注。HDAC6主要定位于细胞质，负责去乙酰化α-微管蛋白和热休克蛋白90（HSP90）等非组蛋白底物，参与调控细胞骨架动力学、蛋白质折叠和降解等过程[91]。与泛HDAC抑制剂相比，靶向HDAC6的PROTAC降解剂能够避免因抑制其他HDAC亚型（如HDAC1/2/3）而导致的严重毒性，如血小板减少和胃肠道反应。临床前研究已证实，HDAC6降解剂在神经退行性疾病和肿瘤动物模型中展现出良好的耐受性和治疗效果，例如，通过降解HDAC6可增强微管稳定性，改善轴突运输，从而在阿尔茨海默病模型中发挥保护作用。此外，HDAC8在T细胞急性淋巴细胞白血病（T-ALL）和神经母细胞瘤中扮演关键角色，其高表达与不良预后相关。与选择性抑制剂相比，HDAC8的PROTAC降解剂能够更彻底地消除其酶活性和潜在的支架功能，从而在体外实验中表现出更强的抗增殖活性，目前该策略仍处于临床前探索阶段[92]。赖氨酸特异性去甲基化酶1（LSD1）是首个被发现的组蛋白去甲基化酶，它通过去除组蛋白H3第4位赖氨酸（H3K4me1/2）上的单甲基和二甲基标记，在基因沉默中发挥核心作用[93]。LSD1在急性髓系白血病（AML）和小细胞肺癌（SCLC）等多种癌症中异常高表达，是驱动肿瘤发生和维持肿瘤干细胞特性的关键因子[94]。研究表明，LSD1不仅通过其去甲基化酶活性调控基因表达，还作为支架蛋白与CoREST、HDAC1/2等形成多蛋白复合物，共同维持染色质的抑制状态[95][96]。传统的LSD1酶活性抑制剂虽然能阻断其催化功能，但无法破坏其支架功能，这可能是其临床疗效有限的原因之一[97]。相比之下，PROTAC降解剂能够通过泛素-蛋白酶体途径将LSD1蛋白完全降解，从而同时去除其酶活性和支架功能，实现更全面的抗肿瘤效应[98]。例如，化合物SJX-1601等LSD1降解剂在动物模型中已显示出显著的抗肿瘤活性，能够有效抑制肿瘤生长并诱导分化[99]。此外，LSD1与HDACs之间存在密切的功能协同作用，联合抑制或降解两者可产生协同抗肿瘤效应，这为开发双靶点降解剂提供了理论基础[100][101][102]。G9a（又称EHMT2）是一种组蛋白甲基转移酶，负责催化H3K9me2的生成，这一修饰通常与基因转录抑制和异染色质形成相关。在肿瘤中，G9a的异常高表达可导致肿瘤抑制基因的沉默，并促进上皮-间充质转化（EMT），从而增强肿瘤细胞的侵袭和转移能力[103]。此外，G9a介导的H3K9me2修饰还参与调控肿瘤微环境中的免疫应答，其活性增加可降低肿瘤细胞的免疫原性，帮助其逃避免疫监视。因此，靶向G9a的蛋白降解策略旨在逆转这些恶性表型。通过PROTAC技术降解G9a，可以更有效地消除其甲基转移酶活性，并可能破坏其与其它染色质调控因子的相互作用，从而更彻底地解除对靶基因的抑制。临床前研究显示，G9a降解剂能够有效抑制肿瘤细胞的EMT过程，并上调MHC-I等免疫相关分子的表达，增强肿瘤细胞对免疫杀伤的敏感性[104]。目前，针对G9a的降解策略仍处于靶点验证阶段，但其在逆转肿瘤恶性表型和增强免疫治疗疗效方面的潜力已引起广泛关注。值得注意的是，LSD1和G9a在功能上存在交叉，例如LSD1通过去甲基化H3K4me1/2与G9a介导的H3K9me2共同维持基因沉默状态，因此，同时靶向这两种酶可能产生协同效应[105]。此外，HDACs与这些去甲基化酶在功能上紧密交织，共同构成了复杂的表观遗传调控网络，例如HDAC5可通过稳定LSD1蛋白来促进乳腺癌进展[106]，而HDAC抑制剂可上调H3K4甲基化水平，部分通过抑制LSD1等去甲基化酶的表达来实现[92]。这些发现强调了开发多靶点或联合降解策略的重要性，以期更有效地干预疾病进程。3.4 其他染色质调节子靶点SMARCA2和SMARCA4是SWI/SNF染色质重塑复合体的核心ATP酶亚基，在多种肿瘤中频繁发生突变。由于SMARCA4在肿瘤中常作为抑癌因子失活，而SMARCA2在SMARCA4缺陷型肿瘤细胞中维持复合体功能，因此靶向SMARCA2在SMARCA4缺陷型肿瘤中具有合成致死效应。PROTAC技术通过同时结合SMARCA2和E3连接酶，诱导其泛素化降解，从而在SMARCA4缺陷型肿瘤细胞中实现选择性杀伤。已有研究报道了如ACBI1等PROTAC分子，在临床前模型中展现出良好的治疗窗口，能够有效抑制SMARCA4缺陷型肿瘤的生长，同时保留对正常细胞的影响较小[107][108]。这种策略利用了肿瘤细胞的遗传依赖性，为治疗SWI/SNF复合体突变的癌症提供了新的思路。BPTF（溴结构域PHD结构域转录因子）是一种重要的染色质修饰因子，通过其溴结构域和PHD结构域识别组蛋白修饰，参与基因转录调控。BPTF在急性髓系白血病和MYCN驱动的神经母细胞瘤中高表达，并促进肿瘤细胞的增殖和存活。针对BPTF的降解剂开发目前处于早期发现阶段，旨在通过PROTAC技术消除其促癌功能。研究表明，降解BPTF可以破坏其与染色质的结合，抑制下游致癌基因的表达，从而抑制肿瘤生长[107][109]。由于BPTF在正常细胞中也具有重要功能，开发高选择性的降解剂以降低脱靶毒性是当前研究的重点。TRIM24（三结构域蛋白24）是一种具有E3连接酶活性的转录共调节因子，通过其多个结构域参与组蛋白修饰和转录调控。TRIM24在乳腺癌等多种肿瘤中过表达，并促进肿瘤进展。PROTAC降解剂通过双功能模式，既可消除TRIM24的转录激活功能，也可调节其E3连接酶活性，从而全面抑制其致癌作用。在乳腺癌模型中，TRIM24降解剂已展示出显著的抗肿瘤效应，通过抑制细胞增殖和诱导凋亡来发挥治疗作用[107][110]。这种双重作用机制使得TRIM24成为极具潜力的治疗靶点，尤其适用于对传统抑制剂耐药的肿瘤。SF3B1（剪接因子3B亚基1）是剪接体U2 snRNP复合体的关键组分，参与前体mRNA的剪接过程。SF3B1基因突变在骨髓增生异常综合征（MDS）中尤为常见，导致异常剪接和肿瘤发生。针对突变型SF3B1的PROTAC降解剂目前处于靶点验证阶段，旨在通过特异性降解突变蛋白来纠正异常剪接。研究表明，降解突变型SF3B1可以恢复正常的剪接模式，抑制MDS细胞的增殖[107][109]。由于SF3B1在正常细胞中不可或缺，开发能够选择性识别突变型蛋白的降解剂是成功的关键。RBM39（RNA结合基序蛋白39）是一种参与RNA剪接的核蛋白，在多种肿瘤中高表达。芳基磺酰胺类分子胶如indisulam通过招募DCAF15 E3连接酶，促使RBM39泛素化降解。这种机制已在急性髓系白血病（AML）的临床试验中得到验证，indisulam等化合物通过降解RBM39抑制肿瘤细胞增殖[107][109]。分子胶降解剂相较于PROTAC具有更小的分子量和更好的药代动力学特性，但其选择性依赖于E3连接酶的表达谱。RBM39降解的成功案例为靶向RNA结合蛋白提供了重要范例，并推动了其他剪接因子降解剂的开发。4. 凋亡与细胞周期蛋白靶点4.1 BCL-2家族抗凋亡蛋白BCL-2家族蛋白是调控线粒体凋亡通路的核心，其抗凋亡成员（如BCL-2、BCL-XL、MCL-1）在多种肿瘤中高表达，是导致肿瘤细胞凋亡抵抗和治疗耐药的关键因素。靶向这些蛋白的PROTAC技术，通过诱导其泛素化降解，为克服传统BH3模拟物的局限性提供了新策略。BCL-XL在血小板和多种实体瘤细胞中均有高表达，其抑制常导致血小板减少症这一剂量限制性毒性。PROTAC降解剂DT2216通过利用肿瘤与血小板中E3连接酶表达的差异，实现了选择性降解肿瘤细胞中的BCL-XL，同时保留血小板。研究表明，DT2216在BRAF V600E结直肠癌中与BRAF抑制剂encorafenib联用，能显著增强凋亡诱导效果，其机制部分依赖于促凋亡蛋白BIM的诱导[111]。此外，在胰腺导管腺癌中，DT2216与MEK抑制剂曲美替尼及EGFR抑制剂阿法替尼组成的三联方案，在抑制肿瘤生长和诱导细胞死亡方面显示出优于双药联合的疗效，且体内耐受性良好[112]。DT2216还被证实可作为有效的衰老细胞清除剂，在治疗诱导的黑色素瘤衰老细胞中，通过靶向BCL-XL克服其抗凋亡适应，其机制涉及下调敏化蛋白HRK并增强BCL-XL与BAK的结合[113]。目前，DT2216已进入I期临床试验阶段，用于多种实体瘤的治疗。BCL-2在慢性淋巴细胞白血病（CLL）中扮演关键角色，其抑制剂维奈托克已取得显著疗效，但获得性耐药，特别是BCL-2 G101V突变，成为临床挑战。为克服这一难题，新型BCL-2抑制剂及PROTAC降解剂正在开发中。例如，BGB-11417（sonrotoclax）作为一种高选择性的BCL-2抑制剂，在临床前研究中展现出优于维奈托克的活性，并能有效抑制包括G101V在内的多种BCL-2突变体。此外，针对CLL中BTK和BCL-2的双重耐药，BTK靶向的PROTAC降解剂（如BGB-16673、NX-2127）与BCL-2抑制剂的联合策略也显示出潜力[114]。在T-幼淋巴细胞白血病中，STAT3/STAT5双降解剂与维奈托克的联合应用也表现出协同效应，能有效降低STAT5磷酸化水平[115]。这些进展表明，通过PROTAC技术直接降解BCL-2蛋白，或联合其他靶向策略，是克服维奈托克耐药的有效途径。MCL-1在骨髓瘤、急性髓系白血病等多种血液肿瘤中高表达，其蛋白质快速周转的特性使得传统抑制剂难以实现持久抑制。PROTAC降解剂通过催化降解模式，能够持续降低MCL-1蛋白水平，从而产生更持久的抗肿瘤效应。例如，一种新型的共降解CK1α和CDK7/9的PROTAC分子13i，在急性髓系白血病细胞中不仅诱导了p53的再激活，还显著下调了包括MCL-1在内的下游基因表达，并降低了炎症因子水平[116]。在BRAF V600E结直肠癌中，尽管BRAF抑制剂能抑制MCL-1表达，但肿瘤细胞仍依赖BCL-XL存活，提示MCL-1与BCL-XL的代偿性抗凋亡机制是联合治疗的关键[111]。此外，针对PI3K p110β亚型的PROTAC降解剂J-6和J-9，通过抑制AKT/Bcl-2通路，诱导内质网应激介导的线粒体凋亡，并抑制P-糖蛋白活性，从而在多药耐药癌细胞中发挥强效抗肿瘤作用[117]。这些研究证实，靶向MCL-1的PROTAC策略能够有效克服其快速周转带来的耐药问题，为治疗MCL-1依赖的血液肿瘤提供了新的希望。4.2 IAP家族抗凋亡蛋白IAP（凋亡抑制蛋白）家族是细胞凋亡调控网络中的关键节点，其成员通过抑制caspase活性及参与多种信号通路来维持细胞存活，在肿瘤发生、发展及耐药中扮演核心角色。该家族在人类中包括XIAP、cIAP1、cIAP2、Survivin、Livin等多个成员，它们通常含有杆状病毒IAP重复（BIR）结构域，这是其发挥抗凋亡功能的关键部位[118][119]。鉴于IAP在肿瘤细胞中的高表达与不良预后密切相关，利用PROTAC技术靶向降解这些蛋白已成为一种极具前景的治疗策略。PROTAC分子通过同时招募目标蛋白和E3泛素连接酶，诱导目标蛋白泛素化并被蛋白酶体降解，从而实现对“不可成药”靶点的干预[120][121]。其中，基于IAP的PROTAC，即特异性非遗传性IAP依赖性蛋白清除剂（SNIPER），通过招募cIAP1或XIAP等E3连接酶，不仅能降解目标致病蛋白，还能同时诱导IAP自身的降解，产生协同抗肿瘤效应[122][123]。cIAP1和cIAP2是IAP家族中具有E3泛素连接酶活性的关键成员，它们通过抑制caspase活性并调节NF-κB信号通路来拮抗凋亡[124][125]。在肿瘤细胞中，cIAP1/2的过表达是导致化疗耐药的重要因素之一[126][127]。PROTAC降解剂的设计思路在于模拟内源性IAP拮抗剂SMAC的功能，通过招募cIAP1/2来诱导其自身泛素化降解，同时解除对caspase的抑制，从而在促进肿瘤细胞凋亡的同时，还能通过激活非经典NF-κB通路诱导促炎细胞因子的分泌[128][129]。例如，化合物AZD5582作为一种高效的SMAC模拟物，能够强效拮抗cIAP1/2和XIAP，在多种血液肿瘤和实体瘤模型中展现出强大的单药活性，通过快速降解cIAP1并诱导肿瘤细胞凋亡来发挥治疗作用[130][127]。此外，研究者还开发了异源双功能PROTAC，通过将IAP拮抗剂与VHL或CRBN配体连接，实现了对cIAP1/2和XIAP的泛降解，这种策略不仅增强了降解效率，还克服了单一IAP拮抗剂可能导致的耐药问题[131][132]。这些研究表明，靶向cIAP1/2的PROTAC策略在模拟SMAC功能的基础上，通过诱导IAP自身降解和激活凋亡通路，为克服肿瘤耐药提供了新的思路。Survivin是IAP家族中结构最为独特的成员，它不仅通过抑制caspase-3和caspase-7的活性来阻断凋亡，还参与调控细胞有丝分裂和血管生成，在多种肿瘤中广泛过表达，并与不良预后和化疗耐药密切相关[133][134][135]。鉴于Survivin在肿瘤发生发展中的多重作用，开发其PROTAC降解剂旨在同时消除其抗凋亡和有丝分裂调控功能，从而更有效地抑制肿瘤生长。研究表明，在耐药性多发性骨髓瘤中，通过PROTAC技术降解Survivin能够显著恢复肿瘤细胞对化疗药物的敏感性，并诱导强烈的凋亡反应[136][137]。目前，针对Survivin的PROTAC降解剂主要处于靶点验证阶段，研究者通过将Survivin抑制剂与IAP或CRBN配体连接，构建了一系列双功能分子[138][139]。这些降解剂在体外实验中显示出对Survivin的高效降解能力，并能有效抑制肿瘤细胞的增殖和克隆形成。然而，由于Survivin在细胞周期中的动态表达和亚细胞定位的复杂性，如何设计出具有高选择性和体内活性的降解剂仍是当前面临的挑战[140][141]。未来的研究需要进一步优化PROTAC分子的连接子长度和E3连接酶选择，以实现对Survivin的持续、高效降解，并评估其在体内模型中的抗肿瘤效果，从而推动其向临床应用转化。4.3 细胞周期蛋白与检查点激酶细胞周期蛋白（Cyclins）与检查点激酶（Checkpoint Kinases）是细胞周期调控网络中的核心组件，其功能紊乱与肿瘤的发生发展密切相关。Cyclin D1、Cyclin A2和Cyclin E1作为关键的细胞周期蛋白，分别驱动G1期进程、S期DNA复制及G2/M期转换。传统的小分子CDK抑制剂虽能阻断这些周期蛋白的活性，但往往因缺乏选择性而导致显著的毒副作用。相比之下，蛋白水解靶向嵌合体（PROTAC）技术通过诱导靶蛋白的泛素化降解，提供了更高的选择性和更持久的抑制作用。研究表明，针对Cyclin D1的PROTAC降解剂在CDK4/6抑制剂耐药的肿瘤模型中展现出卓越的疗效，其机制在于能够同时消除Cyclin D1的激酶依赖性和非依赖性功能，从而克服耐药性[142]。此外，Cyclin E1的过度表达常与基因组不稳定性和不良预后相关，而PROTAC技术能够精准降解这一致癌驱动因子，为治疗Cyclin E1高表达的肿瘤提供了新策略[143]。这些临床前验证结果强调了PROTAC在靶向“不可成药”或“难成药”靶点方面的巨大潜力，有望成为下一代细胞周期靶向治疗的核心工具。WEE1激酶是G2/M检查点的关键调控因子，通过磷酸化CDK1的Tyr15残基来抑制其活性，从而阻止细胞在有丝分裂前进入M期。在p53功能缺失的肿瘤细胞中，G1/S检查点失效，细胞更加依赖G2/M检查点来修复DNA损伤，这为基于WEE1的合成致死策略提供了理论基础[143]。与传统的WEE1抑制剂（如MK-1775）相比，PROTAC介导的WEE1降解具有独特优势：它不仅消除了WEE1的激酶活性，还破坏了其作为支架蛋白的功能，从而更全面地阻断WEE1介导的信号转导[143]。在卵巢癌模型中，WEE1降解剂能够有效诱导DNA损伤积累和有丝分裂灾难，展现出比单纯抑制剂更强的抗肿瘤活性[143]。此外，WEE1的降解还可能影响其与其他蛋白的相互作用，如与PLK1的协同调控，从而进一步放大治疗效果[143]。这些发现表明，通过PROTAC技术靶向WEE1的降解，是一种极具前景的针对p53突变型肿瘤的治疗策略，能够更有效地利用肿瘤细胞的复制应激脆弱性。p53作为“基因组守护者”，其突变是肿瘤中最常见的遗传改变之一。突变型p53蛋白不仅丧失了野生型的抑癌功能，还获得了促进肿瘤侵袭、转移和耐药的新型致癌功能（gain-of-function, GOF）。由于突变型p53蛋白结构稳定性增加，其在肿瘤细胞中持续高表达，成为理想的治疗靶点。PROTAC技术通过设计能够特异性识别突变型p53构象的配体，可以诱导其与E3泛素连接酶结合，进而被泛素-蛋白酶体系统降解[143]。例如，ProtaR-3作为一种代表性的突变型p53降解剂，在多种携带p53突变的肿瘤细胞系中显示出高效的降解活性，并能在动物模型中显著抑制肿瘤生长[143]。降解突变型p53不仅能够消除其GOF活性，还能在某些情况下恢复野生型p53的部分功能，或解除其对p53家族其他成员（如p73）的抑制，从而重新激活凋亡通路[143]。此外，Chk1和Chk2作为DNA损伤检查点激酶，在p53突变型肿瘤中扮演着更为重要的角色，它们与p53信号通路存在复杂的交互调控[144][145]。因此，将突变型p53降解剂与Chk1/Chk2抑制剂联合使用，可能通过协同作用进一步增强对p53突变型肿瘤的杀伤效果，为这类难治性肿瘤提供新的治疗组合。5. 神经变性疾病靶点5.1 蛋白聚集相关靶点Tau（MAPT，微管相关蛋白Tau）在阿尔茨海默病和其他tauopathies中过度磷酸化并聚集，PROTAC降解剂可选择性清除病理形式的Tau，而不影响正常Tau功能。已有转化性策略将细胞穿透肽与PROTAC偶联，在tauopathy小鼠模型中显著减少Tau聚集并改善认知功能。Tau蛋白的异常过度磷酸化及其在神经元内聚集形成神经原纤维缠结，是阿尔茨海默病（AD）及其他tauopathies的核心病理特征。传统小分子药物难以有效靶向这些构象复杂且高度聚集的蛋白，而蛋白水解靶向嵌合体（PROTAC）技术通过利用细胞内泛素-蛋白酶体系统，为选择性清除病理性Tau蛋白提供了全新策略[146][26]。PROTAC分子作为一种异双功能化合物，能够同时招募靶蛋白（如Tau）和E3泛素连接酶，形成三元复合物，进而诱导靶蛋白的多泛素化并被蛋白酶体降解[147]。这一机制的优势在于，它能够特异性地识别并降解过度磷酸化或聚集形式的Tau，而理论上对维持正常微管稳定功能的生理性Tau影响较小，从而避免了完全抑制Tau蛋白可能带来的细胞骨架功能障碍。为了克服PROTAC分子难以穿透血脑屏障（BBB）的挑战，研究者开发了将细胞穿透肽（CPP）与PROTAC偶联的转化性策略。这种偶联物能够显著提高PROTAC在体内的递送效率，使其在tauopathy小鼠模型中有效进入神经元。实验结果显示，经CPP-PROTAC治疗后，小鼠脑内Tau聚集体的水平显著降低，同时伴随着认知功能的改善，这为PROTAC技术在神经退行性疾病中的临床应用提供了有力的概念验证[148]。此外，靶向Tau蛋白的治疗策略还包括抑制其翻译后修饰、促进其降解以及免疫疗法等，而PROTAC技术因其直接降解靶蛋白的独特机制，在克服“不可成药”靶点方面展现出巨大潜力[149]。未来，优化PROTAC分子的选择性、提高其BBB穿透能力以及降低潜在的脱靶毒性，将是推动其向临床转化的关键方向。α-突触核蛋白（SNCA）在帕金森病中形成路易小体，PROTAC降解剂可清除可溶性和聚集性α-突触核蛋白，在动物模型中展示神经保护效果，已有分子通过血脑屏障显示出在皮层区域的降解活性。α-突触核蛋白（α-Synuclein, SNCA）的异常聚集并形成路易小体（Lewy bodies）是帕金森病（PD）的标志性病理改变，其聚集过程涉及从可溶性单体到毒性寡聚体，最终形成不溶性淀粉样纤维的多个阶段[150][151]。α-突触核蛋白的翻译后修饰，如磷酸化、乙酰化、泛素化和硝基化，在其聚集倾向和神经毒性中扮演着关键角色[152]。鉴于α-突触核蛋白的“不可成药”特性，传统药物难以直接作用于其聚集过程，而PROTAC技术为清除这些病理性蛋白提供了新的希望[146]。研究表明，设计合理的PROTAC降解剂能够同时靶向可溶性和聚集形式的α-突触核蛋白，通过泛素-蛋白酶体途径将其降解。在帕金森病的动物模型中，这些PROTAC分子不仅有效降低了脑内α-突触核蛋白的水平，还显著减轻了多巴胺能神经元的损失，并改善了运动功能障碍，展示了明确的神经保护效果[153]。一个关键的突破在于，部分PROTAC分子经过优化后，能够成功穿越血脑屏障，并在大脑皮层等关键区域展现出显著的降解活性。这解决了PROTAC技术在中枢神经系统疾病应用中面临的主要障碍之一。此外，研究还发现，α-突触核蛋白的聚集过程受到多种因素的调控，包括细胞伴侣、金属离子以及核酸等[154][155]。例如，铜伴侣蛋白Atox1可通过形成三元复合物来阻断α-突触核蛋白的聚集[154]。这些发现为设计更高效的PROTAC降解剂提供了新的思路，例如通过结合这些调控机制来增强降解的特异性和效率。尽管目前大多数PROTAC分子仍处于临床前研究阶段，但针对α-突触核蛋白的降解策略已显示出巨大的治疗潜力，有望为帕金森病等突触核蛋白病提供疾病修饰疗法。亨廷顿蛋白（HTT）由CAG重复扩增导致毒性，PROTAC可特异性地降解突变型HTT，保留野生型HTT的功能，已有分子如HTT-PROTAC在亨廷顿病小鼠模型中减少突变蛋白水平并延缓疾病进展。亨廷顿病（HD）是由亨廷顿蛋白（HTT）基因中CAG三核苷酸重复序列异常扩增引起的常染色体显性遗传性神经退行性疾病，其病理核心是突变型HTT（mHTT）蛋白的毒性聚集。由于mHTT与野生型HTT（wtHTT）在结构上高度相似，传统的小分子药物或基因疗法难以实现选择性清除mHTT而不影响wtHTT的正常生理功能，而wtHTT在细胞存活、囊泡运输和转录调控中至关重要。PROTAC技术为解决这一难题提供了精准的解决方案。通过设计能够特异性识别mHTT上由多聚谷氨酰胺（polyQ）扩展所形成独特构象的靶蛋白配体，PROTAC分子可以优先招募mHTT至E3泛素连接酶，从而诱导其泛素化并被蛋白酶体降解，同时最大限度地保留wtHTT的功能[146][26]。研究表明，mHTT的聚集过程受到其N端17个氨基酸片段（NT）的显著影响，该片段在促进淀粉样蛋白成核中起关键作用，而磷酸化修饰（如Ser13/Ser16）可抑制其聚集[156]。基于此，HTT-PROTAC的设计策略可以巧妙地利用mHTT的聚集倾向或特定构象，实现选择性降解。在亨廷顿病小鼠模型中，HTT-PROTAC的给药已显示出显著疗效，能够有效降低脑内mHTT蛋白的水平，减少毒性聚集体的形成，并延缓运动功能障碍和认知衰退等疾病进展[156]。这种策略不仅验证了PROTAC技术在处理由重复序列扩增引起的遗传性疾病中的可行性，也为其他由蛋白聚集驱动的神经退行性疾病（如脊髓小脑性共济失调）提供了可借鉴的模式。然而，挑战依然存在，包括如何进一步提高PROTAC分子对mHTT相对于wtHTT的选择性，以及如何优化其药代动力学特性以实现长期、稳定的脑内递送。TDP-43（TAR DNA结合蛋白43）在肌萎缩侧索硬化症和额颞叶痴呆中异常聚集，PROTAC降解剂可清除细胞质中的毒性TDP-43凝聚体，在细胞和动物模型中展示改善作用的证据。TAR DNA结合蛋白43（TDP-43）是一种核内RNA结合蛋白，在正常情况下主要定位于细胞核，参与RNA的加工和代谢。然而，在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）等神经退行性疾病中，TDP-43发生异常磷酸化、泛素化并从细胞核中错误定位至细胞质，形成毒性聚集体，这是这些疾病的核心病理标志。清除这些细胞质中的TDP-43凝聚体是治疗ALS和FTD的关键策略。PROTAC技术通过利用细胞内固有的泛素-蛋白酶体系统，为直接降解这些病理性TDP-43聚集体提供了有效手段[146][26]。研究显示，针对TDP-43设计的PROTAC降解剂能够有效地将细胞质中的TDP-43聚集体招募至E3泛素连接酶，诱导其泛素化并被蛋白酶体降解。在细胞模型中，这些PROTAC分子显著降低了TDP-43的蛋白水平，并减轻了由其聚集引起的细胞毒性。更重要的是，在ALS和FTD的动物模型中，PROTAC治疗也展现出改善作用，包括减少神经元死亡、减轻神经炎症以及改善运动功能和认知能力[157]。这些结果强有力地证明了PROTAC技术在清除TDP-43病理蛋白方面的潜力。值得注意的是，TDP-43的聚集过程与淀粉样蛋白的形成机制有相似之处，涉及成核、延伸和二级成核等多个步骤[150][158]。因此，通过PROTAC技术直接降解TDP-43，可以从源头上减少聚集体的“种子”，从而抑制整个聚集级联反应。此外，研究还发现，TDP-43的聚集可能与其他蛋白（如FUS）的聚集存在相互作用，共同构成复杂的蛋白互作网络[159]。因此，开发能够同时靶向多种聚集蛋白的PROTAC分子，或与其他治疗策略（如自噬诱导剂）联合使用，可能会产生协同效应，为ALS和FTD等复杂疾病提供更全面的治疗方案。FUS（融合肉瘤蛋白）同样在ALS中形成聚集，其降解剂开发处于早期阶段，已有细胞水平数据显示PROTAC可有效降低FUS蛋白水平。融合肉瘤蛋白（FUS）是一种与TDP-43功能相似的核内RNA结合蛋白，其基因突变是家族性ALS的常见原因之一。在病理状态下，突变的FUS蛋白会从细胞核中异常定位至细胞质，并形成与TDP-43类似的毒性聚集体，参与ALS的发病机制。与TDP-43相比，针对FUS的PROTAC降解剂开发尚处于早期探索阶段，但已有的细胞水平研究已显示出令人鼓舞的结果。初步实验表明，通过合理设计能够特异性结合FUS蛋白的配体，并将其与合适的E3泛素连接酶配体连接，构建的PROTAC分子可以在细胞模型中有效降低FUS蛋白的水平[159]。这一发现为开发针对FUS蛋白病的治疗策略奠定了基础。FUS蛋白的聚集过程同样遵循淀粉样蛋白形成的一般规律，涉及从单体到寡聚体再到纤维的复杂路径[151][160]。因此，通过PROTAC技术直接降解FUS蛋白，理论上可以清除所有形式的毒性物种，包括可溶性寡聚体和不可溶性聚集体。然而，FUS蛋白的降解也面临一些挑战。首先，需要确保PROTAC分子能够特异性地靶向病理形式的FUS（如细胞质中的聚集体），而不影响其正常的核内功能。其次，FUS蛋白的聚集与TDP-43等其他蛋白的聚集可能存在交叉作用，因此，开发高选择性的FUS降解剂至关重要。此外，由于ALS是一种进展迅速的疾病，PROTAC分子需要具备良好的药代动力学特性和中枢神经系统穿透能力，才能实现有效的治疗。尽管目前FUS-PROTAC的研究仍处于概念验证阶段，但已有的细胞数据为后续的动物模型研究和临床转化提供了坚实的科学依据。随着对FUS蛋白结构和聚集机制理解的深入，以及PROTAC设计技术的不断进步，开发出高效、安全的FUS降解剂用于治疗ALS是完全可行的。5.2 神经退行性疾病中的酶靶点在神经退行性疾病领域，针对特定酶的靶向蛋白降解策略正展现出独特的治疗潜力，尤其是在处理由突变蛋白毒性引起的疾病中。以家族性肌萎缩侧索硬化症（ALS）为例，超氧化物歧化酶1（SOD1）的突变是导致该病的重要原因之一。突变型SOD1蛋白会获得异常毒性，并通过错误折叠和聚集引发运动神经元死亡。传统的药物开发策略难以直接靶向并清除这种具有“不可成药性”的突变蛋白。然而，蛋白降解靶向嵌合体（PROTAC）技术为解决这一难题提供了新思路。PROTAC分子能够通过泛素-蛋白酶体系统，特异性地识别并降解突变型SOD1蛋白，从而从源头上消除其毒性[146]。临床前研究已在SOD1-G93A转基因小鼠模型中证实，使用PROTAC降解剂可以有效清除突变型SOD1，并显著延缓模型小鼠的运动功能退化进程。这一成果表明，PROTAC技术不仅为ALS的治疗提供了新的分子工具，也为其他由毒性蛋白聚集引起的神经退行性疾病开辟了新的治疗方向。除了ALS，阿尔茨海默病（AD）也是PROTAC技术的重要应用领域。AD的核心病理特征之一是β-淀粉样蛋白（Aβ）在脑内的异常沉积，而Aβ是由其前体蛋白APP经过β-和γ-分泌酶依次切割产生的。传统的治疗策略多聚焦于抑制这些分泌酶的活性，但长期抑制可能带来严重的副作用。PROTAC技术则提供了一种更为直接的策略：通过设计能够同时结合APP和E3泛素连接酶的双功能分子，直接诱导APP的泛素化降解，从而在源头上减少Aβ的产生。在AD的细胞模型研究中，这种APP靶向的PROTAC降解剂已展现出显著的活性，能够有效降低细胞内的APP水平，并随之减少Aβ40和Aβ42这两种主要毒性肽段的生成[161]。这种直接降解致病蛋白前体的策略，避免了传统酶抑制剂可能引发的代偿性通路激活问题，为AD的疾病修饰治疗提供了更具前景的干预手段。值得注意的是，神经退行性疾病的发病机制极为复杂，涉及多种病理蛋白的异常聚集和功能紊乱。除了直接降解致病蛋白，针对调控这些蛋白代谢的关键酶进行干预也至关重要。例如，在亨廷顿病（HD）中，突变亨廷顿蛋白（mHTT）的毒性作用与多种表观遗传调控酶的异常密切相关。研究表明，mHTT会与蛋白精氨酸甲基转移酶5（PRMT5）相互作用，抑制其活性，导致组蛋白H4R3对称性二甲基化（sDMA）水平降低，进而影响基因转录和RNA剪接，加剧疾病进程[162]。此外，在HD模型中，组蛋白H3K9me3水平升高导致的异染色质异常凝聚也是重要的病理特征，而使用小分子抑制剂APQ靶向组蛋白甲基转移酶SETDB1，可以逆转这一表观遗传异常，改善模型小鼠的运动功能和神经病理症状[163]。这些发现提示，通过PROTAC技术降解那些在神经退行性疾病中功能失调的酶，如PRMT5或SETDB1，同样可能成为一种有效的治疗策略，通过恢复正常的表观遗传景观来发挥神经保护作用。6. 病毒蛋白靶点6.1 乙肝病毒（HBV）靶点乙肝病毒（HBV）感染是全球性的公共卫生挑战，慢性感染可导致肝硬化和肝细胞癌（HCC）的发生[164][165]。在HBV的致病机制中，乙肝病毒X蛋白（HBx）扮演着核心角色。HBx是一个多功能调节蛋白，它通过干扰宿主细胞的DNA损伤修复和转录调控等关键过程，显著促进肝癌的发生与发展。研究表明，HBV感染能够增强细胞的自噬水平，而这一过程正是由HBx所介导的，且不同基因型的HBx（如C型与B型）对自噬的增强程度存在差异，这为理解HBV感染诱发肝癌的机制提供了新思路[166]。此外，HBx还能通过激活磷脂酰肌醇-3-激酶3型（PI3KC3）来启动自噬，从而为HBV自身的DNA复制提供有利条件，这种持续的自噬激活在慢性感染过程中对HBV的致病性至关重要[167]。鉴于HBx在HBV生命周期和肝癌发生中的关键作用，它已成为一个极具吸引力的抗病毒和抗肿瘤药物靶点。传统的抗HBV药物，如核苷（酸）类似物和干扰素，虽然能有效抑制病毒复制，但难以清除核内的共价闭合环状DNA（cccDNA），且对HBx蛋白本身的功能影响有限[168][169]。近年来，蛋白水解靶向嵌合体（PROTAC）技术的出现为靶向降解HBx提供了革命性的策略。PROTAC分子能够通过泛素-蛋白酶体系统特异性地招募并降解目标蛋白，从而消除HBx的多个功能域，包括其反式激活、对DNA损伤修复的干扰以及对细胞信号通路的调控等。与传统的抑制剂不同，PROTAC通过降解整个蛋白而非仅仅抑制其活性位点，理论上可以更彻底地阻断HBx的所有致癌功能，展现出强大的抗病毒和抗肿瘤双重潜力。目前，针对HBx的PROTAC降解剂研究仍处于靶点验证和临床前开发阶段。尽管尚未进入临床试验，但已有的研究为这一策略的可行性提供了有力支持。例如，研究发现HBV核心蛋白（HBc）是Polo样激酶1（PLK1）的底物，而PLK1作为一个促病毒宿主因子，其抑制剂在体内外均能有效抑制HBV复制，这提示靶向宿主因子或病毒蛋白的降解策略具有广阔前景[170]。此外，针对HBV包膜蛋白的研究也表明，通过特定的嵌合抗原受体（CAR）或药物（如蚓激酶同工酶）可以促进乙肝表面抗原（HBsAg）等病毒蛋白的降解，从而抑制病毒复制[171][172]。这些研究共同表明，通过诱导病毒蛋白降解来治疗HBV感染是可行的。未来，随着PROTAC技术的不断成熟和优化，开发出高效、低毒、特异性靶向HBx的降解剂，有望实现慢性乙肝的功能性治愈，即达到HBsAg的持续清除，并显著降低肝癌的发生风险[173]。6.2 人乳头状瘤病毒（HPV）靶点人乳头状瘤病毒（HPV）是导致宫颈癌、头颈癌等多种恶性肿瘤的主要病原体，其致癌作用主要依赖于早期蛋白E6和E7。HPV E6蛋白通过招募E6相关蛋白（E6AP）形成E3泛素连接酶复合物，特异性地靶向并降解肿瘤抑制蛋白p53，从而破坏细胞周期检查点、抑制细胞凋亡，促进基因组不稳定性，最终导致细胞恶性转化[174][175]。针对这一关键致癌机制，蛋白水解靶向嵌合体（PROTAC）技术提供了一种直接清除E6蛋白、间接稳定p53的创新策略。研究表明，通过设计靶向HPV16 E6的PROTAC分子（PROTACE6），能够利用CRL2VHL E3连接酶特异性降解E6蛋白，在HPV阳性宫颈癌的免疫活性小鼠模型中，瘤内注射PROTACE6可显著抑制肿瘤生长，且该抗肿瘤效应依赖于CD4+和CD8+ T细胞介导的宿主免疫应答[176][177]。此外，一种利用病毒E3连接酶（vE3）的VIPER-TAC策略也被提出，该双功能分子可选择性利用HPV编码的E6连接酶降解泛必需蛋白，在HPV阳性宫颈癌细胞中实现特异性杀伤，从而扩大治疗窗口并降低对正常组织的毒性[178]。这些研究证实，通过PROTAC技术直接降解E6蛋白，不仅能恢复p53功能，还能激发抗肿瘤免疫，为HPV相关癌症提供了病毒特异性的治疗新方向。与E6协同作用的HPV E7蛋白同样是关键的致癌驱动因子。E7蛋白通过与视网膜母细胞瘤蛋白（pRb）结合并促进其泛素-蛋白酶体途径降解，解除pRb对E2F转录因子的抑制，从而驱动细胞周期进程，导致细胞无限增殖[179][180]。此外，E7蛋白还能靶向降解多种其他细胞蛋白，如蛋白酪氨酸磷酸酶PTPN14，该蛋白是Hippo信号通路的调节因子，其降解会抑制LATS1激酶活性，减少YAP1的抑制性磷酸化，从而促进YAP1核定位和致癌活性[181][182]。研究表明，在HPV阳性头颈癌模型中，E7蛋白的持续表达是维持肿瘤表型所必需的。通过靶向E7的降解策略，如利用SOCS-1蛋白诱导E7降解，或通过小分子抑制剂阻断E7与pRb的相互作用，可恢复pRb功能，诱导细胞周期阻滞和衰老[183]。此外，E7蛋白还能稳定APOBEC3A蛋白，通过抑制Cullin 2依赖的蛋白降解途径，增加APOBEC3A的细胞半衰期，从而促进HPV阳性癌症中的突变特征[184]。尽管针对E7的PROTAC降解剂开发尚处于早期靶点验证阶段，但已有研究证实，通过降解E7来恢复pRb功能并诱导细胞衰老，在HPV驱动的头颈癌等模型中展现出明确的治疗潜力，为开发新型抗HPV药物提供了重要依据。6.3 SARS-CoV-2冠状病毒靶点SARS-CoV-2主蛋白酶（Mpro）在病毒复制过程中扮演着核心角色，其功能是切割病毒多聚蛋白，产生非结构蛋白以组装复制转录复合体。由于Mpro的活性位点高度保守，传统的小分子抑制剂常因病毒突变而产生耐药性。PROTAC技术通过劫持泛素-蛋白酶体系统（UPS）来降解整个Mpro蛋白，而非仅仅抑制其活性，因此能够有效规避因活性位点突变导致的耐药问题[185]。研究表明，PROTAC分子通过将Mpro招募至E3泛素连接酶，诱导其泛素化并随后被蛋白酶体降解，从而在细胞水平上展现出显著的抗病毒活性[186]。这种降解机制不仅消除了Mpro的酶促功能，还清除了其作为支架蛋白可能参与的其他病毒生命活动，提供了比传统抑制剂更彻底的治疗效果[187]。此外，针对Mpro的PROTAC设计策略已从最初的基于已知抑制剂（如GC376）的探索，发展到利用共价配体进行靶向降解，进一步提高了降解效率和选择性[188]。鉴于Mpro在病毒复制中的不可替代性，开发针对该靶点的PROTAC降解剂被认为是应对SARS-CoV-2及其变异株的极具前景的策略，有望克服当前小分子药物面临的耐药性挑战[189]。SARS-CoV-2核衣壳蛋白（N蛋白）是病毒粒子中含量最丰富的结构蛋白，它不仅负责包装病毒RNA，还参与病毒装配和宿主先天免疫逃逸，是病毒生命周期中的关键多功能蛋白[190]。与靶向病毒入侵或复制酶的策略不同，降解N蛋白可直接抑制病毒颗粒的组装，并解除其对宿主天然免疫的抑制，从而增强机体的抗病毒反应[191]。目前，针对N蛋白的降解策略正处于早期发现阶段。一项研究通过筛选FDA批准的药物库，发现环吡酮（ciclopirox）能够通过间接相互作用诱导N蛋白异常聚集，形成高粘度、低流动性的凝聚体，这些凝聚体随后通过自噬-溶酶体途径被降解，从而显著缩短N蛋白的半衰期并抑制SARS-CoV-2的复制[190]。此外，研究还揭示了病毒通过劫持宿主蛋白稳态机制来调控自身蛋白水平的策略，例如，非结构蛋白NSP12可劫持宿主分子伴侣Hsc70，通过竞争性结合来逃避分子伴侣介导的自噬（CMA）降解，从而促进自身积累和病毒复制[192]。这些发现表明，通过干预宿主-病毒蛋白互作网络来促进N蛋白降解，是开发新型抗病毒药物的有效途径，而PROTAC技术则提供了一种更为直接和可控的降解工具[193]。SARS-CoV-2刺突蛋白（S蛋白）是病毒入侵宿主细胞的关键分子，其S1亚基的受体结合域（RBD）与宿主细胞表面的血管紧张素转换酶2（ACE2）受体结合，介导病毒进入[194]。虽然目前主要的抗病毒策略集中在利用中和抗体阻断S蛋白与ACE2的结合，但PROTAC技术提供了一种全新的细胞内干预手段。研究表明，通过设计靶向S蛋白的PROTAC分子，可以降解细胞内表达的S蛋白，从而减少假病毒颗粒的产生，并在细胞模型中得到了验证[185]。一项研究通过将特异性靶向S1亚基的小肽LCB1与线粒体E3泛素连接酶MUL1偶联，构建了嵌合型E3泛素连接酶LCB1-MUL1，该嵌合酶能够高效催化S1蛋白的K48多泛素化修饰，并加速其通过蛋白酶体降解，将S1蛋白的半衰期从12小时缩短至9小时[195]。此外，研究还发现SARS-CoV-2的包膜（E）蛋白能够与宿主细胞的BET蛋白（BRD2和BRD4）的SEED结构域相互作用，并利用这种特异性相互作用，通过dTAG-SEED融合蛋白系统实现了对E蛋白的选择性降解，这为利用PROTAC技术靶向病毒结构蛋白提供了新的思路[196]。这些研究证实，PROTAC技术不仅能够靶向病毒入侵过程中的关键蛋白，还能通过降解病毒结构蛋白来阻断病毒的生命周期，为开发新型抗SARS-CoV-2药物提供了有力的工具[189]。7. 其他酶与杂项靶点7.1 代谢酶与炎症调节酶IDO1（吲哚胺2,3-双加氧酶1）在肿瘤微环境中通过消耗色氨酸，抑制T细胞功能，从而促进免疫逃逸。传统的IDO1抑制剂如epacadostat虽能阻断其酶活性，但无法消除其非酶活性的免疫抑制功能。PROTAC（蛋白水解靶向嵌合体）技术通过同时降解IDO1蛋白，可彻底消除其酶活性和支架功能，从而更有效地恢复抗肿瘤免疫。在黑色素瘤模型中，IDO1 PROTAC降解剂已展现出优于epacadostat的免疫激活效应，这得益于其能够完全清除IDO1蛋白，而非仅仅抑制其催化活性[197][198]。这种策略通过泛素-蛋白酶体系统（UPS）介导的蛋白降解，克服了传统抑制剂仅能阻断酶活性的局限性，为肿瘤免疫治疗提供了新思路[199][200]。目前，已有多个IDO1靶向的PROTAC分子在临床前验证中显示出强大的降解活性和免疫调节能力，有望成为下一代免疫检查点疗法的重要组成部分[201]。NAMPT（烟酰胺磷酸核糖转移酶）是NAD+补救合成途径中的关键限速酶，在多种肿瘤中高表达，与肿瘤细胞的能量代谢和生存密切相关。传统的NAMPT抑制剂虽能有效抑制其酶活性，但肿瘤细胞可通过获得性突变（如NAMPT基因扩增或点突变）产生耐药性，导致治疗失败。PROTAC降解剂通过诱导NAMPT蛋白的完全降解，能够克服由突变引起的耐药，因为其作用机制不依赖于与突变位点的结合，而是通过招募E3泛素连接酶对NAMPT进行泛素化标记，进而被蛋白酶体降解[197][202]。研究表明，NAMPT PROTAC在多种NAMPT抑制剂耐药的肿瘤细胞系中仍能有效抑制细胞增殖，并诱导细胞凋亡，显示出优于传统抑制剂的抗肿瘤活性[200][201]。这种策略不仅消除了NAMPT的酶活性，还破坏了其可能存在的非酶促功能，从而更全面地阻断NAD+合成通路，为克服靶向治疗耐药性提供了有效手段[198]。HPGDS（造血前列腺素D合酶）催化前列腺素H2（PGH2）转化为前列腺素D2（PGD2），PGD2在过敏反应和炎症性疾病中发挥关键作用。HPGDS的异常表达与哮喘、特应性皮炎等疾病的病理过程密切相关，因此成为治疗这些疾病的重要靶点。传统的HPGDS抑制剂虽能阻断PGD2的合成，但可能无法完全消除其促炎效应，且长期使用可能产生耐药性。PROTAC降解剂通过诱导HPGDS蛋白的完全降解，能够更彻底地阻断PGD2的生成，并可能消除其非酶促功能，从而更有效地控制炎症反应[197][198]。目前，针对HPGDS的PROTAC降解剂仍处于靶点验证阶段，但已有研究证实，通过降解HPGDS蛋白，可以显著抑制过敏原诱导的气道炎症和皮肤炎症反应[201]。这种策略为开发新型抗过敏和抗炎药物提供了新的方向，有望克服传统抑制剂的局限性，为哮喘和特应性皮炎等慢性炎症性疾病患者带来更有效的治疗选择[198]。7.2 磷酸酶与脱甲基化酶PTP1B（蛋白酪氨酸磷酸酶1B）是胰岛素和瘦素信号的负调控因子，降解剂可改善代谢综合征并作为抗肿瘤策略，已有PROTAC分子在葡萄糖耐受不良动物模型中展示效果。蛋白酪氨酸磷酸酶1B（PTP1B）作为胰岛素和瘦素信号通路的经典负调控因子，其通过去磷酸化胰岛素受体及下游底物，抑制胰岛素信号传导，从而在代谢综合征的发病机制中扮演核心角色。在肾脏疾病领域，PTP1B在足细胞中的表达被认为是导致胰岛素抵抗的潜在机制之一，其异常表达与糖尿病肾病的发生发展密切相关[203]。鉴于PTP1B在代谢调控中的关键作用，开发其降解剂已成为一种极具前景的治疗策略。与传统的酶活性抑制剂相比，蛋白水解靶向嵌合体（PROTAC）技术能够通过泛素-蛋白酶体途径诱导PTP1B蛋白的完全降解，从而更彻底地消除其负调控功能。已有研究在葡萄糖耐受不良的动物模型中验证了PTP1B PROTAC分子的有效性，这些分子通过降低PTP1B蛋白水平，显著改善了动物的胰岛素敏感性和葡萄糖耐量，为代谢综合征的治疗提供了新的思路。此外，PTP1B在肿瘤发生中也扮演着复杂角色，其降解策略同样被视为一种潜在的抗肿瘤手段，通过解除对促增殖信号通路的抑制，可能对特定类型的癌症产生治疗效果。尽管PTP1B降解剂在临床前研究中展现出巨大潜力，但其在体内的选择性、药代动力学特性以及长期安全性仍需进一步评估，以推动其向临床转化。PTPN2（蛋白酪氨酸磷酸酶非受体型2）在免疫检查点中抑制T细胞反应，降解剂可增强抗肿瘤免疫，与免疫治疗联用潜力大，目前处于早期发现阶段。蛋白酪氨酸磷酸酶非受体型2（PTPN2）是免疫检查点信号通路中的一个关键负调控因子，主要通过抑制T细胞受体（TCR）信号传导和细胞因子介导的JAK-STAT通路，从而限制T细胞的活化、增殖和效应功能。在肿瘤微环境中，PTPN2的高表达会削弱抗肿瘤免疫应答，导致免疫逃逸。因此，通过降解PTPN2来增强T细胞的抗肿瘤活性，已成为癌症免疫治疗领域的一个新兴策略。与PTP1B类似，利用PROTAC技术靶向降解PTPN2，能够更有效地解除其对免疫细胞的抑制，从而增强机体的抗肿瘤免疫能力。这种策略与现有的免疫检查点抑制剂（如PD-1/PD-L1抗体）联合使用，具有巨大的协同潜力，有望克服部分患者对免疫治疗的原发性和获得性耐药。目前，针对PTPN2的降解剂研究仍处于早期发现阶段，主要集中在靶点验证、降解剂分子的设计与筛选以及初步的生物学功能评估上。尽管尚未进入临床，但已有的概念验证研究显示，PTPN2的降解能够显著增强CD8+ T细胞的杀伤能力，并抑制肿瘤生长。未来的研究重点将包括开发高选择性的PTPN2降解剂，以最大限度地减少对正常细胞中其他磷酸酶信号通路的干扰，并探索其与免疫检查点抑制剂、CAR-T细胞疗法等联合应用的最佳方案。DNMT1（DNA甲基转移酶1）维持DNA甲基化模式，降解剂相比地西他滨等抑制剂更持久地消除异常甲基化，在骨髓增生异常综合征模型中展示活性，已有PROTAC分子在临床前验证。DNA甲基转移酶1（DNMT1）是维持DNA甲基化模式的关键酶，负责在细胞分裂过程中将甲基化模式精确复制到新合成的DNA链上。在多种癌症中，DNMT1的异常高表达导致肿瘤抑制基因启动子区域过度甲基化，从而沉默其表达，促进肿瘤的发生发展。传统的DNMT抑制剂如地西他滨和阿扎胞苷，虽然能够抑制DNMT1的活性，但存在半衰期短、需要持续给药以及脱靶效应等问题。相比之下，靶向DNMT1的蛋白降解策略，特别是PROTAC技术，提供了一种更为持久和彻底的解决方案。通过诱导DNMT1蛋白的降解，可以更有效地消除异常甲基化，并恢复被沉默的肿瘤抑制基因的表达。在骨髓增生异常综合征（MDS）的临床前模型中，DNMT1降解剂已展现出显著的抗肿瘤活性，能够有效逆转异常的DNA甲基化模式，并抑制白血病细胞的增殖。已有多个针对DNMT1的PROTAC分子在临床前研究中得到验证，这些分子通过将DNMT1与E3泛素连接酶拉近，实现对其的特异性泛素化降解。与地西他滨等传统抑制剂相比，DNMT1降解剂不仅能够更持久地降低DNMT1蛋白水平，还能减少因长期抑制酶活性而产生的耐药性。此外，降解剂还可能通过消除DNMT1的非酶学功能（如作为支架蛋白参与转录调控）来增强治疗效果。尽管前景广阔，但DNMT1降解剂的开发仍面临挑战，包括如何提高其口服生物利用度、降低对正常造血干细胞的毒性以及优化其药代动力学特性，以确保其在临床上的安全性和有效性。7.3 分子伴侣与泛素系统蛋白分子伴侣与泛素-蛋白酶体系统（UPS）的协同作用构成了细胞内蛋白质质量控制的核心，而热休克蛋白（HSP）家族作为主要的分子伴侣，在维持蛋白质稳态中扮演着关键角色[204][205]。HSP90α/β是多种激酶和转录因子的分子伴侣，其功能对于肿瘤细胞的存活至关重要。传统的HSP90抑制剂虽能阻断其ATP酶活性，但往往导致热休克因子1（HSF1）的激活，进而代偿性上调其他HSPs，削弱治疗效果。相比之下，利用PROTAC技术降解HSP90可同时消除其伴侣功能和客户蛋白的稳定作用，避免了代偿性反馈，展现出更优的广谱抗肿瘤活性[206][207]。研究表明，HSP90在多种癌症中过表达，其客户蛋白包括雄激素受体、HER2、AKT等关键致癌蛋白，因此HSP90降解剂在去势抵抗性前列腺癌、乳腺癌等模型中显示出强大的抗肿瘤潜力[208][209]。此外，HSP90与共伴侣蛋白cdc37的相互作用对tau蛋白的稳定性和磷酸化动态至关重要，提示HSP90降解策略在神经退行性疾病中也具有潜在应用价值[210]。GRP94（葡萄糖调节蛋白94）是内质网（ER）中的HSP90类似物，与未折叠蛋白反应（UPR）密切相关[211]。在浆细胞骨髓瘤等分泌大量抗体的细胞中，ER应激水平极高，GRP94作为关键的分子伴侣，帮助处理大量未折叠蛋白，维持细胞存活。传统HSP90抑制剂因同时抑制GRP94和HSP90，常导致严重的毒性反应。因此，开发选择性降解GRP94的策略，旨在克服HSP90抑制剂的毒性，同时保留对ER应激的调控能力[212]。GRP94还具有免疫调节功能，能够通过其肽段伴侣能力，结合CD91和Toll样受体（TLRs），激活抗原呈递细胞，从而在妊娠免疫调节和抗肿瘤免疫中发挥作用[211]。靶向GRP94的降解剂有望在浆细胞骨髓瘤等疾病中实现精准治疗，通过消除其促存活功能，同时避免全身性HSP90抑制带来的副作用。VCP（p97，含缬酪肽蛋白）是一种AAA+ ATP酶，在泛素化蛋白质的逆向转位和内质网相关降解（ERAD）中发挥核心作用[204]。VCP通过提取内质网中的错误折叠蛋白，并将其递送至蛋白酶体进行降解，是蛋白质质量控制的关键节点。在VCP突变型肿瘤中，细胞对VCP功能的依赖性增强，因此VCP降解剂具有合成致死效应[213]。已有研究开发出针对VCP的PROTAC分子，并在临床前模型中验证了其抗肿瘤活性。VCP的功能异常还与多种神经退行性疾病相关，如阿尔茨海默病和亨廷顿病，其中错误折叠蛋白的积累与VCP介导的ERAD通路受损有关[214][215]。此外，CHIP（Hsc70羧基末端相互作用蛋白）作为一种关键的E3泛素连接酶，能够与HSP70和HSP90协同作用，将错误折叠蛋白导向UPS降解[216][217]。CHIP的活性受到HSP70的精细调控，这种调控机制对于维持生殖细胞在应激条件下的功能至关重要[217]。因此，靶向VCP和CHIP等分子伴侣与泛素系统的关键节点，为开发新型抗肿瘤和神经退行性疾病治疗策略提供了重要方向[210][218]。7.4 E3连接酶与去泛素酶E3泛素连接酶与去泛素酶（DUBs）是泛素-蛋白酶体系统（UPS）中功能相互拮抗的两类关键酶，共同维持细胞内蛋白质稳态。E3连接酶负责将泛素分子转移至底物蛋白，标记其被26S蛋白酶体降解；而DUBs则通过水解底物上的泛素链，逆转这一过程，从而稳定底物蛋白[219]。这种动态平衡的失调与多种疾病，尤其是癌症的发生发展密切相关[220]。在靶向蛋白降解（TPD）领域，E3连接酶是PROTAC等技术的核心效应元件，而DUBs则既是潜在的耐药机制，也是新兴的治疗靶点[221][222]。因此，深入理解E3连接酶与DUBs的功能及其相互作用，对于开发更有效的TPD策略至关重要。CRBN（cereblon）是免疫调节药物（IMiDs）如来那度胺的分子靶点，作为E3连接酶复合物CRL4CRBN的底物受体，介导了多种新底物的泛素化降解[223]。PROTAC技术正是利用了这一特性，通过设计双功能分子将CRBN招募至目标蛋白，实现对其的靶向降解[224]。然而，在来那度胺治疗中，肿瘤细胞可通过降低CRBN表达或功能来产生耐药性。针对这一挑战，有研究提出通过降解CRBN本身来克服耐药。例如，在骨髓瘤细胞中，利用PROTAC策略降解CRBN，可以消除IMiDs的耐药机制，恢复肿瘤细胞对治疗的敏感性，展示了通过调控E3连接酶自身水平来干预疾病进程的潜力[221]。VHL（von Hippel-Lindau蛋白）是另一种被广泛应用的E3连接酶，它是CRL2VHL复合物的核心组分，在氧感知通路中通过泛素化降解缺氧诱导因子（HIF-α）发挥关键作用[225]。VHL基因的失活突变是遗传性VHL病及散发性肾细胞癌（RCC）的主要病因，导致HIF-α积累，驱动肿瘤发生[226]。针对这一机制，研究者开发了靶向VHL的降解剂。例如，通过设计双功能分子，可以招募并降解突变的VHL蛋白，从而恢复其抑癌功能，或在VHL缺失的肿瘤中，通过降解其他致癌蛋白来抑制肿瘤生长。已有研究报道，这类VHL降解剂在VHL相关肿瘤模型中展现出显著的抗肿瘤活性，为治疗VHL突变导致的肾癌提供了新的思路[226]。MDM2（小鼠双微体2）和MDMX（MDM4）是p53肿瘤抑制蛋白的关键负调控因子。MDM2作为E3连接酶，直接介导p53的泛素化降解，而MDMX则通过与MDM2形成复合物增强其活性[227]。在p53野生型肿瘤中，MDM2/MDMX的过度表达是抑制p53功能、促进肿瘤进展的主要机制。传统的MDM2抑制剂旨在阻断MDM2-p53相互作用，但无法消除MDM2的E3连接酶活性。相比之下，MDM2-PROTAC降解剂提供了一种更彻底的策略，它不仅能阻断MDM2与p53的结合，还能通过泛素-蛋白酶体途径将MDM2蛋白本身降解，从而同时消除其E3连接酶功能和转录调控功能[228]。这种双重作用机制能够更有效地激活p53信号通路，诱导肿瘤细胞凋亡。已有多种MDM2-PROTAC分子在临床前研究中展现出强大的抗肿瘤活性，为p53野生型肿瘤的治疗带来了新的希望[228]。7.5 其他重要靶点β-Catenin（β-连环蛋白）在Wnt信号通路中作为关键的转录共激活因子，其异常激活与多种癌症，尤其是结直肠癌的发生发展密切相关。PROTAC技术通过设计异源双功能分子，能够同时结合β-Catenin和E3泛素连接酶，诱导β-Catenin的泛素化及随后的蛋白酶体降解，从而有效干预经典Wnt信号通路。在结直肠癌模型中，这类降解剂已展现出显著的抗肿瘤活性，通过抑制Wnt/β-catenin信号传导，进而抑制肿瘤细胞的增殖和迁移[229]。然而，β-Catenin蛋白本身具有较高的稳定性，其结构复杂且缺乏明确的“热点”结合口袋，这给高效降解剂的设计带来了巨大挑战。此外，β-Catenin在正常细胞中也发挥重要的生理功能，因此，设计具有高度选择性的PROTAC分子以避免脱靶毒性，是当前研究的重点和难点。GSPT1（G1-期到S-期转换蛋白1）是一种关键的翻译终止因子，在蛋白质合成的终止阶段发挥核心作用。在血液肿瘤中，GSPT1的过度表达或功能异常与肿瘤细胞的增殖和存活密切相关。分子胶水如CC-90009能够诱导GSPT1与E3泛素连接酶CRBN的异常相互作用，导致GSPT1的泛素化降解。这种部分降解策略在急性髓系白血病（AML）的临床试验中已显示出诱导肿瘤细胞凋亡的显著效果[4][230]。与传统的PROTAC不同，分子胶水通常具有更小的分子量和更优的药代动力学特性，但其作用机制依赖于诱导蛋白-蛋白相互作用，因此其设计更具挑战性。CC-90009的成功为靶向GSPT1等“不可成药”靶点提供了新的思路，并推动了针对其他血液肿瘤的分子胶水药物的开发。PD-L1（程序性死亡配体1）是肿瘤细胞表面介导免疫逃逸的关键分子，通过与T细胞表面的PD-1受体结合，抑制T细胞的抗肿瘤活性。传统的抗体药物虽然能有效阻断PD-L1/PD-1相互作用，但存在组织渗透性差、生产成本高等局限性。PROTAC技术为降解PD-L1提供了新的途径，通过设计PROTAC分子，可以靶向并降解细胞内的PD-L1蛋白，从而减少其在细胞表面的表达，恢复T细胞的杀伤功能[231]。已有研究报道，特定的PROTAC分子在动物模型中能够有效降低PD-L1水平，并显著增强T细胞介导的肿瘤杀伤效果。这种策略不仅克服了抗体药物的局限性，还可能通过同时降解膜结合型和可溶型PD-L1，实现更全面的免疫抑制解除。然而，如何确保PROTAC分子特异性地在肿瘤细胞中降解PD-L1，避免对正常免疫细胞造成影响，是未来研究需要解决的关键问题。USP7和USP14是泛素特异性蛋白酶家族中的重要成员，它们作为去泛素化酶，能够去除底物蛋白上的泛素链，从而阻止蛋白被蛋白酶体降解。在肿瘤细胞中，USP7和USP14的过度表达会导致肿瘤抑制蛋白如p53的稳定性降低，促进肿瘤的发生发展。通过设计PROTAC分子靶向降解USP7或USP14，可以增强p53等抑癌蛋白的稳定性，从而诱导肿瘤细胞凋亡或细胞周期停滞[56]。临床前研究已证实，多个靶向USP7或USP14的PROTAC分子在多发性骨髓瘤和神经母细胞瘤模型中展现出显著的抗肿瘤活性。这些研究不仅验证了去泛素化酶作为TPD靶点的可行性，也为治疗这些难治性肿瘤提供了新的候选药物。然而，由于去泛素化酶家族成员众多且功能复杂，如何实现高选择性降解以避免潜在的毒性，仍是该领域面临的重大挑战。miR-21是一种在多种癌症中高表达的致癌microRNA，通过调控多个下游靶基因，促进肿瘤细胞的增殖、迁移和侵袭。传统的靶向miRNA的策略，如反义寡核苷酸，存在稳定性差、递送效率低等问题。RIBO-TAC（核糖核酸靶向嵌合体）技术是一种新兴的非蛋白级别的TPD策略，它通过设计双功能分子，一端结合靶标miRNA，另一端招募核糖核酸酶，从而实现对miRNA的特异性降解[232]。在肝癌细胞模型中，靶向miR-21的RIBO-TAC分子已成功诱导miR-21的降解，并展现出显著的抗肿瘤活性。这一策略突破了传统TPD技术仅能靶向蛋白的局限，将降解范围扩展至非编码RNA，为治疗由miRNA驱动的疾病提供了全新的思路。尽管RIBO-TAC技术仍处于早期发展阶段，但其在靶向“不可成药”RNA靶点方面的巨大潜力，预示着其在未来精准医疗中将扮演重要角色。8. 降解策略与新药管线分析8.1 PROTAC技术的主流策略在靶向蛋白降解（TPD）领域，蛋白水解靶向嵌合体（PROTAC）技术已成为最具代表性的策略之一。其核心在于通过一个异双功能分子同时招募目标蛋白（POI）和E3泛素连接酶，诱导POI泛素化并被蛋白酶体降解[233][234]。目前，PROTAC分子的设计高度依赖于对特定E3连接酶配体的选择，其中基于CRBN（Cereblon）配体的PROTAC占据了主导地位，约占已报道分子的60%。CRBN配体，如来那度胺及其衍生物（统称为“环酰亚胺类”），因其良好的药物化学性质、相对较小的分子量以及出色的口服生物利用度而备受青睐[235][236]。这些配体能够高效地招募CRBN，形成稳定的三元复合物，从而驱动靶蛋白的泛素化。例如，针对BRD4、CDK9等靶点的PROTAC分子，许多都采用了CRBN配体，并在临床前和临床研究中展现出强大的降解活性和抗肿瘤效果[237][238]。CRBN配体的广泛适用性使其成为PROTAC设计的首选，推动了多个候选药物进入临床试验阶段[239][240]。相比之下，基于VHL（von Hippel-Lindau）配体的PROTAC约占30%。VHL配体源自HIF-1α的羟脯氨酸衍生物，其与VHL的结合具有高度的特异性和较强的亲和力，这赋予了VHL-based PROTAC出色的降解活性和选择性[241][242]。然而，VHL配体通常具有更高的极性，导致其口服生物利用度相对较低，这在一定程度上限制了其临床转化潜力[243]。尽管如此，VHL配体在实现选择性降解方面仍具有独特优势。例如，通过结构指导的设计，研究人员开发了能够选择性降解SMARCA2而非其高度同源的SMARCA4的VHL-recruiting PROTAC，并在体内模型中验证了其疗效，证明了VHL配体在实现精准靶向降解方面的价值[242]。此外，对VHL配体的共价修饰策略也被探索，以扩展其应用范围并提高降解效率[241]。为了克服现有E3连接酶配体（如CRBN和VHL）的局限性，并实现更广泛的组织特异性或细胞条件性降解，研究人员正积极开发新型E3连接酶。例如，通过DNA编码化合物库（DEL）技术或基于活性的蛋白质谱分析（ABPP），已成功发现了靶向TRIM21、RNF4、DCAF1、DCAF11和GID4等新型E3连接酶的小分子配体[244][245][246][247][248]。这些新型E3连接酶的组织特异性表达模式（如TRIM58在红系前体细胞中特异性表达）为实现更精准的降解提供了可能[249]。此外，一些非传统的策略也被提出，例如开发不依赖E3连接酶，而是直接招募26S蛋白酶体亚基Rpn13的ByeTACs，或者通过酶激活的“糖衣”PROTAC（SCPs）来实现对降解活性的时空控制[250][251]。这些新兴策略极大地扩展了PROTAC技术的工具箱，为未来开发更安全、更有效的靶向蛋白降解疗法奠定了基础[252][253]。8.2 分子胶与PROTAC的互补分子胶降解剂与PROTAC在机制上存在根本性的互补，这种互补性不仅体现在作用模式上，更体现在对靶点空间的拓展和临床策略的协同上。分子胶通过重塑E3泛素连接酶（如CRBN）的表面，诱导其与原本无相互作用的蛋白（新底物）结合，从而引发泛素化降解[254]。经典案例如来那度胺，它通过与CRBN结合形成新的蛋白-蛋白相互作用界面，从而招募并降解转录因子IKZF1和IKZF3[255][256]。这种机制高度依赖三元复合物的形成，其设计比PROTAC更具挑战性，因为分子胶的发现历史上多源于偶然，而非理性设计[257][258]。然而，这种独特的机制也赋予了分子胶更高的特异性，因为它依赖于靶蛋白表面特定的结构特征（如β-发夹结构）来形成稳定的三元复合物[259]。在靶点覆盖方面，分子胶展现出对“难以成药”靶点的独特优势，尤其是转录因子等缺乏传统小分子结合口袋的蛋白。例如，分子胶降解剂已成功靶向IKZF2、RBM39和GSPT1等转录相关蛋白，这些靶点对于传统抑制剂而言极具挑战性[260][261]。其中，靶向GSPT1的分子胶降解剂已进入临床管线，显示出在血液肿瘤中的治疗潜力[262]。此外，分子胶还能降解RNA结合蛋白如Lin28，其效率甚至优于PROTAC，这进一步拓展了可药性蛋白组[263]。这种能力源于分子胶通过稳定弱蛋白-蛋白相互作用来发挥作用，从而能够靶向那些表面平坦、缺乏深疏水口袋的蛋白[264][265]。PROTAC和分子胶的联合使用策略正在成为克服耐药性和实现多靶点协同降解的前沿方向。由于两者都依赖泛素-蛋白酶体系统，但通过不同的机制招募E3连接酶，因此可以设计出同时包含PROTAC和分子胶功能的多重降解剂。例如，同时靶向BRD4和IKZF1/3的双功能降解剂已在临床前研究中得到验证，这种策略通过同时降解多个关键致癌蛋白，能够更有效地抑制肿瘤生长并延缓耐药性的产生[266]。此外，将PROTAC与免疫调节药物（IMiD）结合，可以同时降解目标蛋白（如BTK）和IKZF1/3，实现协同抗肿瘤效应，代表性分子如NX-2127已在临床试验中展现出克服BTK抑制剂耐药的潜力[266]。这种互补策略不仅扩大了治疗窗口，还为应对肿瘤异质性和动态耐药机制提供了新的解决方案[267][7]。8.3 新兴TPD技术管线LYTAC（溶酶体靶向嵌合体）技术通过偶联抗体识别细胞表面受体（如CI-M6PR）和靶蛋白，介导溶酶体降解，用于清除细胞外或膜蛋白，已有靶向EGFR、PD-L1的LYTAC在临床前验证。该技术突破了传统PROTAC仅能降解胞内蛋白的局限，将TPD的应用范围扩展至膜蛋白及胞外蛋白，这些蛋白在信号转导、免疫调节及疾病发生中扮演关键角色[231]。LYTAC的设计原理是利用溶酶体靶向受体（如CI-M6PR）将结合了靶蛋白的复合物内化并递送至溶酶体进行降解，从而实现对细胞表面或分泌蛋白的特异性清除[4]。临床前研究已证实，靶向EGFR的LYTAC能够有效降解肿瘤细胞表面的EGFR，抑制下游信号通路，展现出抗肿瘤潜力；同时，靶向PD-L1的LYTAC则可通过降解免疫检查点蛋白，增强抗肿瘤免疫应答[232]。这些成果表明，LYTAC技术为治疗由膜蛋白异常表达或功能失调引起的疾病（如癌症、自身免疫性疾病）提供了全新的策略，有望克服传统抗体药物或小分子抑制剂面临的耐药性和靶点局限性问题[268]。AUTAC（自噬靶向嵌合体）利用自噬标签（如p62蛋白结合域）引发靶蛋白自噬性降解，适用于细胞质内聚集蛋白如突变型亨廷顿蛋白，已在小鼠模型中展示神经系统效果。与依赖泛素-蛋白酶体系统的PROTAC不同，AUTAC通过模拟自噬受体（如p62）的功能，将靶蛋白招募至自噬体，进而与溶酶体融合实现降解[4]。这一机制使其特别适用于降解那些难以被蛋白酶体识别的大分子蛋白聚集体、受损细胞器以及具有聚集倾向的致病蛋白，例如在亨廷顿病中由突变型亨廷顿蛋白形成的聚集体[232]。在小鼠模型中，AUTAC技术已成功降低了脑内突变型亨廷顿蛋白的水平，并改善了相关的神经病理学和行为学表型，显示出其在治疗神经退行性疾病方面的巨大潜力[268]。此外，AUTAC技术也为清除其他与蛋白质聚集相关的疾病（如阿尔茨海默病、帕金森病）中的致病蛋白提供了新的思路，其作用机制与细胞自噬过程的天然调控网络相契合，有望实现更精准的病理蛋白清除[56]。RIBOTAC（核糖核酸靶向嵌合体）将RNA配体与RNase L结合物偶联，降解靶miRNA或lncRNA，miR-21降解剂已展示抗肿瘤潜力，属于非蛋白TPD范式的拓展。RIBOTAC技术将TPD的概念从蛋白质拓展至RNA分子，通过设计嵌合分子，一端特异性结合目标RNA（如致癌miR-21），另一端招募并激活内源性核糖核酸酶RNase L，从而实现对特定RNA的催化降解[232]。这一策略为靶向传统上“不可成药”的非编码RNA提供了有效工具，这些RNA在多种疾病（尤其是癌症）中发挥关键的调控作用[268]。例如，针对miR-21的RIBOTAC降解剂已在多种癌细胞模型中显示出显著的抗肿瘤活性，通过降低miR-21水平，解除其对肿瘤抑制基因的抑制，从而抑制细胞增殖并诱导凋亡[4]。RIBOTAC技术的出现，标志着TPD领域从蛋白质降解向更广泛的生物分子调控迈出了重要一步，为开发针对RNA层面的新型治疗策略开辟了道路，尤其适用于那些由非编码RNA驱动或参与的复杂疾病[56]。8.4 临床管线概况与趋势截至2024年，全球靶向蛋白降解（TPD）领域已取得显著进展，超过30个TPD药物进入临床试验阶段，其中PROTAC约15个，分子胶约20个，主要集中在肿瘤领域[4]。这一趋势反映了TPD技术从概念验证向临床转化的加速，尤其是在血液系统恶性肿瘤和实体瘤中展现出巨大潜力[64]。领先管线如ARV-110（bavdegalutamide，一种雄激素受体降解剂）已进入II期临床，而ARV-471（vepdegestrant，雌激素受体降解剂）在临床试验中显示出良好的安全性和意向性客观缓解率，为激素受体阳性乳腺癌患者提供了新的治疗选择[254]。这些PROTAC药物的成功推进，验证了通过劫持泛素-蛋白酶体系统催化降解致病蛋白的可行性，并克服了传统小分子抑制剂因靶点突变或功能冗余导致的耐药性问题[269]。在分子胶领域，CC-90009（一种GSPT1降解剂）在急性髓系白血病（AML）的I/II期临床中展示了单药活性，而第二代分子胶CC-92480（IKZF2/3降解剂）通过进一步提高选择性，有望降低脱靶毒性并增强疗效[262]。分子胶通过重塑E3连接酶表面，诱导与新生底物的相互作用，从而实现对传统“不可成药”靶点的降解，这一机制已在临床前和临床研究中得到验证[270]。值得注意的是，尽管大多数TPD管线聚焦于肿瘤学，但神经退行性疾病和自身免疫病领域的TPD管线也在增加，例如针对Tau蛋白的降解剂和RIPK2降解剂已开始从临床前向临床转化[271]。这些进展表明，TPD技术的应用范围正在从癌症扩展到更广泛的疾病领域，包括神经退行性疾病、炎症性疾病和纤维化疾病[272][273]。然而，TPD药物的临床转化仍面临多重挑战，包括口服生物利用度低、组织选择性不足、以及潜在的“Hook效应”和脱靶毒性[267]。此外，目前大多数临床阶段的TPD药物依赖于有限的E3连接酶（如CRBN和VHL），这限制了其靶点覆盖范围[274]。未来，通过开发新型E3连接酶配体、优化连接子设计以及利用纳米递送系统，有望进一步提升TPD药物的疗效和安全性[275]。总体而言，TPD临床管线的快速扩展标志着该领域正从理论探索迈向实际应用，为患者提供了前所未有的治疗机会。9. 挑战与未来方向9.1 口服生物利用度与药代动力学PROTAC分子因其独特的双功能结构，通常具有较大的相对分子质量（常超过800 Da）和较多的氢键供体，这使其显著超越了经典的“类药五规则”（Lipinski’s Rule of Five）[276]。这种超越规则（bRo5）的物理化学特性，直接导致了PROTAC分子普遍面临口服吸收差、代谢快速清除等严峻的药代动力学挑战[276][277]。研究表明，大多数PROTAC候选药物在开发初期就因其固有的理化性质，在口服生物利用度、系统暴露量以及靶点部位的蓄积能力上受到显著限制，这成为制约其临床转化的主要瓶颈之一[278]。例如，对已进入临床的PROTAC药物ARV-110的放射性ADME研究显示，其在无食物状态下的大鼠口服生物利用度仅为10.75%，即便在食物辅助下也仅提升至20.97%，远低于传统小分子药物的理想水平[279]。尽管其口服吸收不佳，但ARV-110在低剂量下仍展现出优于传统抑制剂恩杂鲁胺的治疗效果，这凸显了PROTAC事件驱动型药理学的独特优势，即其催化降解机制使得高口服生物利用度并非产生卓越疗效的必要前提[279]。为了克服口服生物利用度这一核心障碍，研究者们探索了多种策略。一方面，通过结构修饰和药物设计来优化PROTAC分子的物理化学性质，例如开发分子量更低的疏水标签降解技术（HyTs），这类分子因其相对较小的分子量而具备更好的口服生物利用度潜力[280]。另一方面，药物递送系统的引入为解决这一难题提供了新的思路。纳米技术介导的靶向蛋白降解（nano-TPD）通过改善药物的药代动力学、组织分布和细胞摄取，有望提升PROTAC的治疗指数[278][281]。此外，基于前药策略的共价修饰、多头的PROTAC设计以及微针递送系统等创新方法，也旨在提高PROTAC的溶解性和细胞渗透性，从而改善其体内降解效率和降低脱靶毒性[282]。这些策略的核心目标是在不牺牲PROTAC降解活性的前提下，优化其ADMET（吸收、分布、代谢、排泄和毒性）特性，使其更符合口服药物的开发要求[276]。值得注意的是，尽管PROTAC面临诸多药代动力学挑战，但业界普遍认为，对PROTAC的DMPK/ADME评价在本质上与其他bRo5化合物并无根本差异，只是需要在传统小分子药物的评估流程基础上进行适当修改[276]。例如，需要开发定制化的体外分析方法来精确评估PROTAC的溶解度、非特异性结合等关键参数[283]。同时，对三元复合物稳定性、E3连接酶和靶蛋白的表达水平、再合成速率以及泛素化效率等细胞参数的深入理解，对于合理设计具有理想药代动力学特性的PROTAC至关重要[221][284]。未来，结合人工智能和机器学习进行ADMET预测，以及探索组织特异性递送策略，将是推动PROTAC从实验室走向临床应用的关键方向[276][285]。9.2 选择性调控与脱靶效应靶向蛋白降解（TPD）技术，特别是PROTACs和分子胶，通过劫持泛素-蛋白酶体系统来消除致病蛋白，为治疗癌症等疾病提供了革命性的策略[286][287]。然而，这种强大的机制也伴随着固有的选择性挑战和脱靶效应风险。一个关键问题在于，单个PROTAC分子可能并非完全特异性地作用于目标蛋白，它也可能降解E3连接酶本身（如UBR4、NEK2等），或通过形成非预期的三元复合物而降解其他非目标蛋白，从而引发非预期的表型变化[288][289]。这种“脱靶降解”不仅可能削弱治疗效果，还可能带来严重的细胞毒性。例如，在靶向表观遗传调控因子的PROTACs开发中，尽管通过结构优化实现了对特定HDAC亚型（如HDAC3、HDAC6）的选择性降解，但仍有必要通过严谨的蛋白质组学分析来全面评估其脱靶谱，以确保其治疗窗口[64][290]。分子胶降解剂由于其作用机制依赖于重塑E3连接酶表面以诱导与目标蛋白的蛋白-蛋白相互作用，其选择性难题更为突出[291][273]。与PROTACs通过两个独立的配体分别结合E3连接酶和目标蛋白不同，分子胶的“胶水”作用高度依赖于复杂的、动态的蛋白-蛋白界面，这使得其设计更具挑战性，也更容易产生非预期的降解活性[292][293]。例如，免疫调节药物（IMiDs）作为经典的分子胶，除了降解其治疗靶点（如IKZF1/3）外，还能降解多种新底物，这既是其疗效的来源，也是其副作用（如致畸性）的根源[294][295]。因此，对于分子胶降解剂，必须采用更全面的蛋白质组学方法，如定量蛋白质组学，来系统性地鉴定其所有降解底物，从而在早期发现并规避潜在的脱靶毒性[296][297]。为了应对这些选择性挑战，研究人员正在开发多种优化策略。首先，基于结构的理性设计至关重要，通过解析PROTAC与目标蛋白和E3连接酶形成的三元复合物结构，可以指导优化连接子的长度、组成和连接位点，从而稳定预期的三元复合物，并减少非特异性相互作用[298][299]。其次，利用肿瘤微环境或特定细胞类型的特征，开发刺激响应型PROTACs，例如利用癌细胞中高浓度的谷胱甘肽（GSH）来激活PROTAC前药，从而在肿瘤部位实现选择性降解，减少对正常组织的脱靶效应[272][300]。此外，探索利用更多样化的E3连接酶，特别是那些在特定组织或疾病中高表达的E3连接酶，也有望提高降解的选择性[301][302]。最后，将先进的蛋白质组学技术，如热蛋白质组分析（TPP）和泛素化蛋白质组学，整合到药物发现流程中，已成为评估和优化TPD分子选择性的关键工具，能够全面揭示其降解图谱和潜在的非预期靶点[303][304]。9.3 耐药机制与适应症拓展肿瘤细胞对靶向蛋白降解（TPD）疗法产生耐药性的机制复杂多样，其中下调功能性E3连接酶活性或激活自噬等补救途径是核心环节。研究表明，TPD的疗效高度依赖于特定E3连接酶（如CRBN、VHL）的表达水平与功能状态。当肿瘤细胞通过表观遗传沉默、基因突变或蛋白降解途径降低这些关键E3连接酶的表达时，PROTAC或分子胶降解剂（MGD）便无法有效招募E3连接酶来泛素化靶蛋白，从而导致降解失败[58]。此外，肿瘤细胞还可能通过激活自噬-溶酶体途径来补偿蛋白酶体功能的不足，从而抵抗TPD诱导的蛋白降解。例如，mTOR信号通路的激活被证实可增强蛋白合成，为被降解的靶蛋白提供“补给”，从而削弱TPD的疗效；反之，抑制mTOR信号则能显著增强多种蛋白酶体依赖性TPD药物的降解效率，并恢复对来那度胺等MGD的敏感性[58]。这种通过调节蛋白合成速率来对抗降解的机制，揭示了TPD耐药中一个关键的代谢脆弱性。为了预测和克服这些耐药机制，精准的患者选择和联合治疗策略至关重要。首先，通过生物标志物（如E3连接酶的表达水平、mTOR通路活性状态）对患者进行分层，可以识别出最可能从TPD治疗中获益的人群。例如，在复发/难治性多发性骨髓瘤患者中，mTOR抑制剂与MGD的联合应用已显示出恢复药物敏感性的潜力[58]。其次，联合治疗是克服耐药的主流方向。将TPD药物与免疫检查点抑制剂（如PD-1/PD-L1抗体）联用，有望通过降解肿瘤细胞内的免疫抑制蛋白（如PD-L1）来重塑肿瘤微环境，增强抗肿瘤免疫应答[60]。此外，针对肿瘤特异性抗原的嵌合抗原受体T细胞（CAR-T）疗法，也可通过结合TPD技术进行精准调控，例如利用来那度胺控制的化学遗传系统来时空可控地增强CAR-T细胞的细胞因子信号，从而提升其持久性和抗肿瘤活性[305]。这种将TPD与免疫疗法相结合的思路，为治疗实体瘤和克服免疫治疗耐药提供了新范式。适应症的拓展是TPD领域发展的另一重要方向。除了在血液肿瘤中已取得的临床成功，TPD技术正逐步向实体瘤、神经退行性疾病及感染性疾病等领域渗透。在实体瘤中，尽管面临组织穿透性和肿瘤异质性等挑战，但针对特定驱动基因（如EGFR、AR）的PROTAC已进入临床前或早期临床阶段[306]。例如，针对EGFR抑制剂耐药的结直肠癌，使用能强力诱导EGFR内化和降解的抗体混合物Sym004，在临床I期试验中显示出显著的抗肿瘤活性，验证了即使存在耐药突变，肿瘤仍可能依赖EGFR信号通路的假说[307]。在非肿瘤领域，TPD技术也展现出巨大潜力。例如，在神经退行性疾病中，利用PROTAC或分子胶降解异常聚集的蛋白（如Tau蛋白、α-突触核蛋白）被认为是极具前景的治疗策略[271]。在感染性疾病中，通过设计靶向病毒蛋白或细菌毒力因子的PROTAC，可以克服传统抗生素的耐药性问题[308]。此外，TPD技术还被探索用于组织再生，例如通过SMARCA2靶向的PROTAC降解剂选择性促进辐射损伤后唾液腺上皮的再生，而不促进口腔鳞癌的生长，这为放疗后组织损伤的修复提供了全新的“再生而不促癌”策略[309]。这些跨领域的探索，极大地拓展了TPD技术的应用边界，预示着其将从单一的肿瘤治疗工具，演变为调控蛋白质稳态的通用平台技术。结论TPD技术正从概念验证阶段加速迈向临床转化，其核心价值在于突破了传统小分子抑制剂“可成药性”的局限，将药物作用边界拓展至转录因子、表观遗传调控因子及聚集蛋白等“不可成药”靶点。通过对216个热门靶点的系统梳理，我们清晰地看到，TPD在激酶领域已展现出克服耐药性的独特优势，在核受体和转录因子领域则填补了传统药物设计的空白，而在神经退行性疾病和病毒蛋白领域，尽管面临血脑屏障透过性等挑战，但动物模型中的积极数据已为未来治疗提供了全新路径。然而，TPD技术的临床转化并非坦途。口服生物利用度、选择性、耐药机制及高通量筛选方法仍是制约其发展的核心瓶颈。不同研究在靶点选择、降解效率及毒性评估上存在显著差异，例如，部分PROTAC分子在体外表现出高效降解，但在体内因药代动力学特性不佳而效果有限。因此，平衡不同研究的观点，需从“靶点-分子-疾病”三维度综合考量：优先选择具有明确生物学验证的靶点，优化分子设计以兼顾降解效率与药代特性，并针对特定疾病模型进行差异化验证。未来，TPD技术的突破将高度依赖计算机辅助设计与蛋白组学技术的深度融合。通过AI驱动的分子设计优化口服生物利用度，结合蛋白组学解析耐药机制，有望实现从“广谱降解”向“精准调控”的跨越。这216个靶点的系统性梳理，不仅为当前药物开发提供了靶点优先级参考，更揭示了TPD技术从“概念验证”到“临床价值”转化的关键路径——唯有在靶点选择、分子设计与临床需求之间找到最佳平衡点，才能真正释放TPD技术的治疗潜力。参考文献[1] 王蔚, 盛春泉. 靶向蛋白降解技术的开发之路[J]. 海军军医大学学报, 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The Journal of Infectious Diseases. Volume 233 Issue 1 传染病杂志 233卷 1期 https://academic.oup.com/jid/issue/ Editorial（社论） 1 Virulent Bacteriophages for Controlling Shiga Toxin–Producing Escherichia coli (STEC) Without Inducing Toxin Production 用于控制产志贺毒素大肠杆菌（STEC）且不诱导毒素产生的烈性噬菌体 Glen D Armstrong The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 1–2, https://doi.org/10.1093/infdis/jiaf036 Invited Perspective（特邀观点） 2 With All Good Intentions: How CDC Decisions Harmed Science and People John Weiser 好心办坏事：美国疾控中心（CDC）的决策如何损害了科学和民众 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 3–5, https://doi.org/10.1093/infdis/jiaf584 Perspectives（观点） 3 Persistence Is Resistance: The Fight to End the HIV Epidemic Hangs in the Balance 坚持即抵抗：结束艾滋病流行的斗争悬而未决 Colleen F Kelley and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 6–8, https://doi.org/10.1093/infdis/jiaf389 Special Collection on Contemporary Research on Antimicrobial Resistance（抗菌药物耐药性当代研究特辑） Call for Papers: Antimicrobial Resistance（征稿启事：抗菌药物耐药性） 4 How Pooled Procurement Can Expand Access to Novel Antibacterial Therapeutics Globally 集中采购如何在全球范围内扩大新型抗菌疗法的可及性 Jessica Swenson The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 9–15, https://doi.org/10.1093/infdis/jiaf370 5 Pharmacokinetics and Safety of Clofazimine in Women With Rifampicin-resistant Tuberculosis During Pregnancy and the Postpartum Period: Results From IMPAACT P1026s 妊娠期及产后利福平耐药结核病女性患者使用氯法齐明的药代动力学和安全性：IMPAACT P1026s研究结果 Jennifer A Hughes and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 16–26, https://doi.org/10.1093/infdis/jiaf504 6 Emergence of ST3390: A Novel Apigmented MRSA Clone From the CC5 Lineage ST3390的出现：源自CC5谱系的一种新型非色素性耐甲氧西林金黄色葡萄球菌克隆 Emily A Felton and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 27–37, https://doi.org/10.1093/infdis/jiaf410 7 Establishing a Practical Approach to Sewer Monitoring for Antimicrobial Resistance Genes and Organisms at Healthcare Facilities 建立医疗机构针对抗菌药物耐药基因和耐药菌的污水监测实用方法 Rachel S Poretsky and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 38–48, https://doi.org/10.1093/infdis/jiaf434 8 Real-world Prevalence of Nonintegrase INSTI Resistance-Associated Mutations and Virological Outcomes in People Who Have Recently Acquired HIV-1 in the United Kingdom 英国近期感染HIV-1人群中非整合酶INSTI耐药相关突变的现实流行率及病毒学结果 Christine Kelly and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 49–58, https://doi.org/10.1093/infdis/jiaf500 9 Detection of Carbapenem-Resistant Bacteria in Skilled Nursing Facility Wastewater 在专业护理机构废水中检测碳青霉烯类耐药细菌 Susanna Lenz and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 59–69, https://doi.org/10.1093/infdis/jiaf534 10 Investigating Azithromycin Activity Against ESBL-Producing Escherichia coli Under Physiologically Relevant Conditions 在生理相关条件下研究阿奇霉素对产超广谱β-内酰胺酶大肠杆菌的活性 Sean Jung and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 70–75, https://doi.org/10.1093/infdis/jiaf480 ID Translational Science Update（传染病转化医学更新） 11 Planning and Analyzing a Low-Biomass Microbiome Study: A Data Analysis Perspective 低生物量微生物组研究的规划与分析：数据分析视角 George I Austin and Tal Korem The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 76–86, https://doi.org/10.1093/infdis/jiae378 Major Articles and Brief Reports（主要论著和简短报告） Bacterial Disease Pathogenesis（细菌性疾病发病机制） 12 Virulent Bacteriophages for Controlling Shiga Toxin–Producing Escherichia coli Without Inducing Toxin Production 用于控制产志贺毒素大肠杆菌（STEC）且不诱导毒素产生的烈性噬菌体 Eunshin Cho and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 87–95, https://doi.org/10.1093/infdis/jiaf035 13 Hygromycin A Treatment of Borrelia burgdorferi–Infected Peromyscus leucopus Suggests Potential as a Reservoir-Targeted Antibiotic 对伯氏疏螺旋体感染的白足鼠使用潮霉素A治疗，提示其作为针对储存宿主抗生素的潜在作用 Stephanie S You and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 96–100, https://doi.org/10.1093/infdis/jiaf363 14 Low Intrinsic Killing Activity and no Impact of Its Positivity on Phase 3 Pneumococcal Vaccine Adult Studies 固有杀菌活性低，且其阳性对3期肺炎球菌疫苗成人研究无影响 Weifeng Xu and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 101–111, https://doi.org/10.1093/infdis/jiaf427 15 Population Structure of Escherichia coli Isolated From the Human Bloodstream, Human and Animal Feces, and the Environment in Northern Tanzania 坦桑尼亚北部从人体血液、人和动物粪便以及环境中分离出的大肠杆菌的种群结构 Deng B Madut and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 112–121, https://doi.org/10.1093/infdis/jiaf437 Viral Disease Pathogenesis（病毒性疾病发病机制） 16 Evaluating the Breadth and Reliability of Influenza Vaccine Protection Indicators: A Secondary Analysis of an Animal Challenge Trial 评估流感疫苗保护指标的广度和可靠性：动物挑战试验的二次分析 Yao Lu and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 122–131, https://doi.org/10.1093/infdis/jiaf331 17 Assessing the Transmissibility and Outbreak Risk of Measles in the United States, 2024–2030 评估2024 - 2030年美国麻疹的传播性和暴发风险 Subekshya Bidari and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 132–136, https://doi.org/10.1093/infdis/jiaf342 18 Coronavirus Disease 2019 Risk in Patients With Autoimmune Diseases Using Biologics or Small Molecules: A Population-Based Cohort Study 使用生物制剂或小分子药物治疗的自身免疫性疾病患者感染2019冠状病毒病的风险：一项基于人群的队列研究 Eun Mi Song and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 137–147, https://doi.org/10.1093/infdis/jiaf347 19 Leveraging Lyme Disease Surveillance to Simulate Powassan Virus Prevalence 利用莱姆病监测来模拟伯氏疏螺旋体脑炎病毒流行率 James M McCluskey and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 148–152, https://doi.org/10.1093/infdis/jiaf368 20 Human Metapneumovirus–, Respiratory Syncytial Virus–, and Influenza-Associated Pneumonia Hospitalizations in Colorado Adults Aged ≥50 Years, 2016–2023 2016 - 2023年科罗拉多州50岁及以上成年人中与人类偏肺病毒、呼吸道合胞病毒和流感相关的肺炎住院情况 Eric A F Simões and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 153–163, https://doi.org/10.1093/infdis/jiaf381 Malaria Disease Pathogenesis（疟疾发病机制） 21 Digital PCR Reveals High PvDBP1 but not PvEBP/DBP2 and PvRBP2b Copy Number in Plasmodium vivax From Duffy-Negative Individuals in Central Africa 数字PCR显示，在非洲中部杜菲血型阴性个体中，恶性疟原虫的PvDBP1拷贝数高，但PvEBP/DBP2和PvRBP2b拷贝数不高 Bernis Neneyoh Yengo and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 164–172, https://doi.org/10.1093/infdis/jiaf322 22 Elevated Soluble Urokinase-Type Plasminogen Activator Receptor Levels, Organ Dysfunction, and Death in Children Hospitalized With Malaria: Considerations for Use as a Risk Stratification Tool 疟疾住院儿童中可溶性尿激酶型纤溶酶原激活物受体水平升高、器官功能障碍和死亡：作为风险分层工具的考量 Charles Ssuuna and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 173–177, https://doi.org/10.1093/infdis/jiaf327 23 Vaccine-Induced Antibodies to a C-Terminal Plasmodium falciparum Circumsporozoite Protein Epitope Associated With Protection Against Malaria Challenge 疫苗诱导产生的针对疟原虫环子孢子蛋白C端表位的抗体与对疟疾挑战的保护作用相关 DeAnna J Friedman-Klabanoff and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 178–190, https://doi.org/10.1093/infdis/jiaf391 24 Cytokines Associated With Moderate and Severe Adverse Events During a Sporozoite Malaria Vaccine Trial With Controlled Human Malaria Infection 在受控人体疟疾感染的孢子虫疟疾疫苗试验中，与中度和重度不良事件相关的细胞因子 Lauren P Jatt and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 191–196, https://doi.org/10.1093/infdis/jiaf435 Global Health（全球健康） 25 HIV and Syphilis Coinfection in Pregnancy and Adverse Birth Outcomes in Uganda 乌干达妊娠期HIV和梅毒合并感染与不良出生结局 Mehal Churiwal and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 197–205, https://doi.org/10.1093/infdis/jiaf453 26 Antibodies to Tick Salivary Antigens AV422 and Calreticulin in Patients With Spotted Fever Group Rickettsioses and Other Febrile Illnesses in Northern Tanzania 坦桑尼亚北部斑点热群立克次体病及其他发热性疾病患者体内针对蜱唾液抗原AV422和钙网织蛋白的抗体 Ganga S Moorthy and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 206–215, https://doi.org/10.1093/infdis/jiaf506 27 Virological Tools Fail to Properly Identify “Unusual” Hepatitis C Virus Subtypes Resistant to Direct-Acting Antiviral Drugs in The Gambia 病毒学工具未能正确识别冈比亚对直接抗病毒药物耐药的“罕见”丙型肝炎病毒亚型 Erwan Vo-Quang and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages 216–220, https://doi.org/10.1093/infdis/jiaf378 Major Articles and Brief Reports（主要论著和简短报告） Public Health（公共健康） 28 A Framework for Assessing the Opportunity for Advanced Research, Development, and Regulatory Approval of Medical Countermeasures: A Component of BARDA's Emerging Infectious Diseases Strategy 评估医疗对策先进研究、开发和监管批准机会的框架：生物医学高级研究与发展管理局（BARDA）新兴传染病战略的组成部分 Richard C White and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e1–e10, https://doi.org/10.1093/infdis/jiaf486 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 29 Prevalence of Candidate Vaccine Targets and Genomic Features of Pediatric Invasive Streptococcus Agalactiae in Japan 日本儿科侵袭性无乳链球菌候选疫苗靶点的流行率及基因组特征 Masashi Kasai and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e11–e21, https://doi.org/10.1093/infdis/jiaf491 30 Daptomycin-Loaded Nanocarriers Facilitate Synergistic Killing of Methicillin-Resistant Staphylococcus aureus via Lipid-Mediated Interactions and Targeting 载达托霉素纳米载体通过脂质介导的相互作用和靶向作用促进对耐甲氧西林金黄色葡萄球菌的协同杀伤 Jhih-Hang Jiang and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e22–e33, https://doi.org/10.1093/infdis/jiaf492 31 Comparing Respiratory Illness Surveillance Case Definitions to Detect Bordetella pertussis in Children Aged <5 Years With Respiratory Illness in South Africa, 2017–2023 Kate Bishop and others 比较呼吸道疾病监测病例定义以检测2017 - 2023年南非5岁以下呼吸道疾病患儿中的百日咳博德特氏菌 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e34–e43, https://doi.org/10.1093/infdis/jiaf501 32 Insights on Recurrent and Sequential Clostridioides difficile Infections From Genomic Surveillance in Minnesota, USA, 2019–2021 2019 - 2021年美国明尼苏达州基因组监测对复发性及序贯性艰难梭菌感染的见解 Daniel Evans and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e44–e54, https://doi.org/10.1093/infdis/jiaf505 33 Single-Cell Transcriptome Profiling Reveals the Immune Dysregulation Characteristics of Mice Infected With Brucella abortus 单细胞转录组分析揭示感染牛布鲁氏菌小鼠的免疫失调特征 Guangzhi Zhang and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e55–e66, https://doi.org/10.1093/infdis/jiaf522 34 Culture and Adaptation of Pseudomonas aeruginosa During Early Infection in Children With Cystic Fibrosis 囊性纤维化患儿早期感染期间铜绿假单胞菌的培养与适应 Sumitra D Mitra and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e67–e76, https://doi.org/10.1093/infdis/jiaf527 Viral Disease Pathogenesis（病毒性疾病发病机制） 35 Hyperendemicity of Rift Valley Fever in Southwestern Uganda Associated With the Rapidly Evolving Lineage C Viruses 乌干达西南部裂谷热高度流行与快速进化的C谱系病毒相关 Barnabas Bakamutumaho and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e77–e88, https://doi.org/10.1093/infdis/jiaf417 36 Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccination Against Hospitalizations and Deaths According to Frailty Score: A Post Hoc Analysis of the DANFLU-1 Randomized Trial 根据衰弱评分比较高剂量与标准剂量流感疫苗对住院和死亡的相对有效性：DANFLU - 1随机试验的事后分析 Caroline Espersen and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e89–e98, https://doi.org/10.1093/infdis/jiaf420 37 Emergence of Two New Lineages of the Cosmopolitan Dengue Virus Serotype 2 in Yunnan, China, 2024 2024年中国云南出现两种新的全球流行性登革热病毒2型谱系 Man Li and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e99–e108, https://doi.org/10.1093/infdis/jiaf422 38 Cerebrospinal Fluid Immune Cell Alterations in Women With Neuropsychiatric Long COVID 神经精神性新冠长期症状女性患者脑脊液免疫细胞改变 Benjamin Orlinick and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e109–e117, https://doi.org/10.1093/infdis/jiaf468 39 The Role of Enoxaparin in Influenza Virus Infections and its Therapeutic Implications 依诺肝素在流感病毒感染中的作用及其治疗意义 Marta Bermejo-Jambrina and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e118–e131, https://doi.org/10.1093/infdis/jiaf470 40 Monkeypox Virus Shedding Despite Tecovirimat Treatment in a Cohort in Toronto, Canada 加拿大多伦多一队列中接受特考韦瑞治疗后猴痘病毒仍排出的情况 Jacklyn R Hurst and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e132–e139, https://doi.org/10.1093/infdis/jiaf471 41 Disentangling Temporal Trends of Clade Ib Monkeypox Virus Transmission in Burundi 厘清布隆迪Ib支系猴痘病毒传播的时间趋势 Shihui Jin and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e140–e144, https://doi.org/10.1093/infdis/jiaf475 42 Profiling Human Papillomavirus Lineage-Specific Capsid Antigenicity With Geographically Diverse Natural Infection Antibodies 利用地理多样性自然感染抗体剖析人乳头瘤病毒谱系特异性衣壳抗原性 Kavita Panwar and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e145–e150, https://doi.org/10.1093/infdis/jiaf502 43 Respiratory Virus Infections and Pulmonary Impairment After Allogeneic Hematopoietic Cell Transplantation 异基因造血细胞移植后呼吸道病毒感染与肺功能损害 Guang-Shing Cheng and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e151–e163, https://doi.org/10.1093/infdis/jiaf503 Antimicrobial Resistance (AMR)（抗菌药物耐药性） 44 Insights Into Global Antimicrobial Resistance Dynamics Through the Sequencing of Enteric Bacteria From US International Travelers 通过对美国国际旅行者肠道细菌测序洞察全球抗菌药物耐药性动态 Sushmita Sridhar and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e164–e173, https://doi.org/10.1093/infdis/jiaf469 45 The Burden of Surgical Site Infections With Pathogens Presumably Resistant to Perioperative Prophylaxis in Orthopedic Tumor Surgery: Secondary Analysis of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) Trial 骨科肿瘤手术中疑似对围手术期预防用药耐药的手术部位感染负担：肿瘤手术预防性抗生素方案（PARITY）试验的二次分析 Sabine Kuster and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e174–e182, https://doi.org/10.1093/infdis/jiaf513 46 Foreign Combatants Wounded in Ukraine Colonized by Extensively Drug-Resistant Organisms: A Potential Source of Global Dissemination 在乌克兰受伤的外国战斗人员被广泛耐药菌定植：全球传播的潜在来源 Patrick Mc Gann and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e183–e191, https://doi.org/10.1093/infdis/jiaf538 HIV/AIDs（HIV/艾滋病） 47 Long-Acting Antiretroviral Therapy for Breastfeeding Women With HIV Experiencing Barriers to Adherence in Zimbabwe: Modeling Clinical Impact and Cost-effectiveness 针对津巴布韦存在依从性障碍的感染HIV的哺乳期妇女采用长效抗逆转录病毒疗法的临床影响和成本效益建模 Sujata E Tewari and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e192–e202, https://doi.org/10.1093/infdis/jiaf521 48 Resistance Analyses of Lenacapavir, Emtricitabine/Tenofovir Alafenamide and Emtricitabine/Tenofovir Disoproxil Fumarate in the PURPOSE 1 and 2 Studies PURPOSE 1和2研究中来那卡帕韦、恩曲他滨/丙酚替诺福韦和恩曲他滨/富马酸替诺福韦二吡呋酯的耐药性分析 Stephanie Cox and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e203–e211, https://doi.org/10.1093/infdis/jiaf533 49 Resistance Analysis of Low-Level Virologic Rebound During HIV-1 Treatment With Lenacapavir and Broadly Neutralizing Antibodies Teropavimab and Zinlirvimab 使用来那卡帕韦和广谱中和抗体特罗帕维单抗及津利瑞单抗治疗HIV - 1期间低水平病毒学反弹的耐药性分析 Lisa Selzer and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e212–e220, https://doi.org/10.1093/infdis/jiaf559 50 IL-4 Correlates With Bone Mineral Density in Men, and IL-4 Depletion May Drive Bone Loss in Men With HIV 白细胞介素 - 4与男性骨矿物质密度相关，白细胞介素 - 4耗竭可能导致感染HIV男性骨丢失 Ighovwerha Ofotokun and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e221–e229, https://doi.org/10.1093/infdis/jiaf570 Correspondence（读者来信） 51 External Validation of Pediatric Pneumonia and Bronchiolitis Risk Scores to Predict Mortality in Children Hospitalized in Kenya: A Retrospective Cohort Study 儿科肺炎和毛细支气管炎风险评分在预测肯尼亚住院儿童死亡率方面的外部验证：一项回顾性队列研究 Becky Gordon and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e230–e238, https://doi.org/10.1093/infdis/jiaf377 52 Seroprevalence of Antibodies Against Legionella Species in Northeastern Australian Blood Donors, 2016 and 2023 2016年和2023年澳大利亚东北部献血者中针对军团菌属抗体的血清阳性率 Juniper Lethbridge and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e239–e249, https://doi.org/10.1093/infdis/jiaf407 53 Diagnostic Performance and Kinetics of Hepatitis E Viral RNA and IgM Antibody Test Positivity in a Genotype 1 Outbreak in South Sudan 南苏丹1型基因型戊型肝炎病毒暴发期间戊型肝炎病毒RNA和IgM抗体检测阳性的诊断性能和动力学 Aybüke Koyuncu and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e250–e258, https://doi.org/10.1093/infdis/jiaf436 54 Leptospirosis Prevalence and Risk Factors Among Patients Presenting With Fever to 4 Healthcare Sites in Sub-Saharan Africa and South East Asia: An International Multisite Observational and Nested Case–Control Study 撒哈拉以南非洲和东南亚4个医疗站点发热患者中钩端螺旋体病的流行率和危险因素：一项国际多站点观察性和嵌套病例对照研究 John A Crump and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e259–e270, https://doi.org/10.1093/infdis/jiaf464 55 Refined Transgenic Mouse Models Which Recapitulate the Natural Features of Chronic Wasting Disease With Rapid Prion Disease Onsets 改良转基因小鼠模型可快速引发朊病毒病并重现慢性消耗性疾病的自然特征 Joseph P DeFranco and others The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e271–e276, https://doi.org/10.1093/infdis/jiaf529 Correction（更正） 56 Correction to: Monocytes and Macrophages, Targets of Severe Acute Respiratory Syndrome Coronavirus 2: The Clue for Coronavirus Disease 2019 Immunoparalysis 更正：单核细胞和巨噬细胞——严重急性呼吸综合征冠状病毒2的靶点：2019冠状病毒病免疫麻痹的线索 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Page e277, https://doi.org/10.1093/infdis/jiaf622 Editor's Note（编者按） 57 Editor's Note: Bartonella quintana Bacteremia and Overproduction of Interleukin-10: Model of Bacterial Persistence in Homeless People 编者按：五日热巴尔通体菌血症和白细胞介素 - 10过度产生：无家可归者细菌持续存在的模型 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Page e278, https://doi.org/10.1093/infdis/jiaf623 58 Editor's Note: Oral Ivermectin in the Treatment of Body Lice 编者按：口服伊维菌素治疗体虱 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Page e279, https://doi.org/10.1093/infdis/jiaf627 JID 2025 Reviewer Recognition（《传染病杂志》2025年审稿人认证） 59 2025 JID Reviewer Recognition List 2025年《传染病杂志》审稿人认证名单 The Journal of Infectious Diseases, Volume 233, Issue 1, 15 January 2026, Pages e280–e286, https://doi.org/10.1093/infdis/jiag015 The Journal of Infectious Diseases. Volume 233 Issue 2 传染病杂志 233卷 2期 https://academic.oup.com/jid/issue/ Editorials（社论） 1 2025 Content Collections from the IDSA Journals 2025年美国感染病学会（IDSA）期刊内容合集 Roger Bedimo and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 221–222, https://doi.org/10.1093/infdis/jiag041 2 “Fostemsavir: More Than Meets the Eye” “福替沙韦：不止于表面所见” Siddharth Kogilwaimath and Netanya S Utay The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 223–226, https://doi.org/10.1093/infdis/jiaf462 3 On-Demand Dosing of HIV Preexposure Prophylaxis for Women: Has Their Time Finally Come? 女性按需服用艾滋病病毒暴露前预防药物：时机是否已到？ Susan P Buchbinder and Peter L Anderson The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 227–229, https://doi.org/10.1093/infdis/jiaf507 Invited Perspective（特邀观点） 4 The Changing Paradigm in Infectious Diseases—Host-Directed Medicine: Implications for the Next Generation of ID Physicians 感染性疾病领域的范式转变——宿主导向疗法：对下一代传染病医师的影响 Jatin M Vyas and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 230–234, https://doi.org/10.1093/infdis/jiaf497 Invited ID Translational Science Update（特邀传染病转化医学更新） 5 Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host-Directed Therapy 以色氨酸代谢为靶点，开发结核病生物标志物和宿主导向疗法 Jeffrey M Collins and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 235–243, https://doi.org/10.1093/infdis/jiaf510 6 Clinical Commentary on: Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host-Directed Therapy 关于“以色氨酸代谢为靶点，开发结核病生物标志物和宿主导向疗法”的临床评论 Joel D Ernst The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 244–246, https://doi.org/10.1093/infdis/jiaf624 Major Articles and Brief Reports（主要论著与简要报告） HIV/AIDs（人类免疫缺陷病毒/艾滋病） 7 Fostemsavir Decreases the Levels of Anti-gp120 CD4-Induced Antibodies in Heavily Treatment-Experienced People With HIV 福替沙韦可降低经治重度HIV感染者体内抗gp120 CD4诱导抗体的水平 Mehdi Benlarbi and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 247–256, https://doi.org/10.1093/infdis/jiaf461 8 Optimizing On-Demand Tenofovir Disoproxil Fumarate/Emtricitabine Dosing in Women for HIV Prevention 优化女性按需服用富马酸替诺福韦二吡呋酯/恩曲他滨预防HIV感染的剂量 Nathan Engel and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 257–260, https://doi.org/10.1093/infdis/jiaf459 9 Cabotegravir and Rilpivirine Concentrations and HIV-1 RNA Suppression in Genital Fluids and Rectum in People with HIV on Long-Acting Intramuscular Cabotegravir Plus Rilpivirine Antiretroviral Therapy 接受长效肌肉注射卡博特韦加利匹韦林抗逆转录病毒治疗的HIV感染者生殖道分泌物和直肠中的卡博特韦和利匹韦林浓度及HIV-1 RNA抑制情况 Analuz Fernández and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 261–266, https://doi.org/10.1093/infdis/jiaf551 10 Elimination of Human Immunodeficiency Virus Reservoirs Harboring Intact Proviruses 清除携带完整前病毒的HIV储存库 Min Li and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 267–277, https://doi.org/10.1093/infdis/jiaf373 11 Vaccination Against Pathogens Targeting Cell-Derived Cryptic Antigens 针对细胞来源的隐蔽抗原的病原体疫苗接种 Emily S Clark and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 278–286, https://doi.org/10.1093/infdis/jiaf593 12 NAT2 Polymorphisms and Antituberculosis-Induced Hepatotoxicity in Thai People Living With HIV: Insights From a Pharmacogenetic–Pharmacokinetic Cohort Study 泰国HIV感染者NAT2基因多态性与抗结核治疗所致肝毒性的关系：一项药物基因组学-药代动力学队列研究的见解 Napon Hiranburana and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 287–297, https://doi.org/10.1093/infdis/jiaf511 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 13 Interplay between Tetanus, Diphtheria, Acellular Pertussis Vaccination in Pregnancy and Infant Pneumococcal Vaccination in Shaping Infant Pneumococcal Vaccine Serotype Carriage 孕期接种破伤风、白喉、无细胞百日咳疫苗与婴儿接种肺炎球菌疫苗对婴儿肺炎球菌疫苗血清型携带的影响 Eline Van den Bosch and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 298–306, https://doi.org/10.1093/infdis/jiaf458 14 Role of Activin A–Mediated KAT8 Expression in Regulating Ferroptosis During Mycobacterium tuberculosis Infection Activin A介导的KAT8表达在结核分枝杆菌感染中调节铁死亡的作用 Bijewar Ashish Satish and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 307–318, https://doi.org/10.1093/infdis/jiaf482 15 Phospholipid Transporter MlaFEDCB Regulates Klebsiella pneumoniae Virulence by Modulating Fimbriae Synthesis and Stress-adaptive Growth 磷脂转运蛋白MlaFEDCB通过调节菌毛合成和应激适应性生长来调控肺炎克雷伯菌的毒力 Xiaoyu Zhao and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 319–327, https://doi.org/10.1093/infdis/jiaf517 16 Novel KPC-2 Plasmid in a Clinical Salmonella Rissen Selected by Antibiotic Pressure 抗生素压力下临床沙门氏菌里森氏菌中新型KPC-2质粒的出现 María Aznar Fernández and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 328–333, https://doi.org/10.1093/infdis/jiaf536 Viral Disease Pathogenesis（病毒性疾病发病机制） 17 Respiratory Syncytial Virus Fusion Protein Epitope-Specific Antibodies and Neutralizing Activities Against Various Respiratory Syncytial Virus Strains 呼吸道合胞病毒融合蛋白表位特异性抗体对多种呼吸道合胞病毒株的中和活性 Hisao Okabe and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 334–341, https://doi.org/10.1093/infdis/jiaf375 18 Clinical and Environmental Surveillance of Poliovirus Type 2 Outbreak Using a Novel Specific Real-time Quantitative Polymerase Chain Reaction Assay, Israel, 2022–2023 2022-2023年以色列利用新型特异性实时定量聚合酶链反应检测法对2型脊髓灰质炎病毒疫情进行临床和环境监测 Itay Bar-Or and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 342–350, https://doi.org/10.1093/infdis/jiaf387 19 Robust COVID-19 Mortality Risk Assessment: Validation of a Two-Step Algorithm From the National COVID Cohort Collaborative 稳健的COVID-19死亡风险评估：国家COVID队列协作组织的两步算法验证 Bingnan Li and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 351–362, https://doi.org/10.1093/infdis/jiaf393 20 Histone Deacetylase 6 Regulates α-Tubulin to Inhibit the Stimulator of Interferon Genes/NLR Family Pyrin Domain-Containing 3-Mediated Microglial Pyroptosis Induced by Herpes Simplex Virus Type 1 Infection 组蛋白去乙酰化酶6调节α-微管蛋白，抑制1型单纯疱疹病毒感染诱导的干扰素基因刺激因子/NLR家族含吡啶结构域蛋白3介导的小胶质细胞焦亡 Qiongzhen Zeng and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 363–374, https://doi.org/10.1093/infdis/jiaf404 Parasites（寄生虫） 21 Schistosome Infection is Associated With High-Risk Human Papillomavirus Persistence, Together With Altered Cervicovaginal Microbiota 血吸虫感染与高危型人乳头瘤病毒持续感染及宫颈阴道微生物群改变相关 Crispin Mukerebe and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 375–380, https://doi.org/10.1093/infdis/jiaf447 22 The Source-Sink Dynamics of Plasmodium vivax May Undermine Malaria Elimination Efforts in the Amazon: An Epidemiological and Population Genomic Study 恶性疟原虫的源-汇动态可能破坏亚马逊地区疟疾消除工作：一项流行病学和群体基因组学研究 Nathalia Rammé M de Albuquerque and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 381–390, https://doi.org/10.1093/infdis/jiaf457 23 Seasonal Variation and Interspecies Dynamics Among Plasmodium falciparum and ovale Species in Bagamoyo, Tanzania 坦桑尼亚巴加莫约地区恶性疟原虫和卵形疟原虫的季节性变化及种间动态 Kelly Carey-Ewend and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 391–400, https://doi.org/10.1093/infdis/jiaf498 24 Genome Sequencing of Leishmania tropica in Tissues of Moroccan Patients Reveals Microfocal Transmission Underlain by (Pseudo)Clonal and Sexual Reproduction 摩洛哥患者组织中利什曼原虫热带种的基因组测序揭示了（假）克隆和有性繁殖导致的微灶性传播 Othmane Daoui and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 401–410, https://doi.org/10.1093/infdis/jiaf485 25 Trichomonas vaginalis Among Cisgender Women Taking Doxycycline Postexposure Prophylaxis 顺性别女性服用多西环素暴露后预防药物期间的阴道毛滴虫感染情况 Fredericka Albertina Sesay and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages 411–415, https://doi.org/10.1093/infdis/jiaf519 26 A BEACON for Novel Disease Threats: Leveraging Artificial Intelligence for Informal Event-Based Outbreak Surveillance 应对新型疾病威胁的“灯塔”：利用人工智能进行非正式事件疫情监测 Nahid Bhadelia and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e287–e289, https://doi.org/10.1093/infdis/jiaf642 Major Articles and Brief Reports（主要论著与简要报告） Bacterial Disease Pathogenesis（细菌性疾病发病机制） 27 Chlamydia trachomatis-specific T Cell Immunity Reflects Widespread Exposure in South African Adolescents and Young Women 沙眼衣原体特异性T细胞免疫反映南非青少年和年轻女性广泛暴露情况 Rubina Bunjun and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e290–e300, https://doi.org/10.1093/infdis/jiaf595 28 Serum IgG1 and IgG3 Antibodies to Chlamydia trachomatis Pgp3 and Hsp60 in Men of Subfertile Couples 不育夫妇男性体内针对沙眼衣原体Pgp3和Hsp60的血清IgG1和IgG3抗体 Tiina Holster and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e301–e310, https://doi.org/10.1093/infdis/jiaf535 29 Publicly Available Neisseria Gonorrhoeae Genomes Predominantly Represent In Vitro-Derived Nonpiliated Variants 公开可用的淋病奈瑟菌基因组主要代表体外衍生的非菌毛变异体 Iryna Boiko and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e311–e321, https://doi.org/10.1093/infdis/jiaf557 30 Signal Transducers and Activators of Transcription 1 (STAT1), STAT2, and T Cells Mediate Interferon-Dependent Protection Against Neurobrucellosis 信号转导和转录激活因子1（STAT1）、STAT2和T细胞介导干扰素依赖性抗神经布鲁氏菌病的保护作用 Charles R Moley and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e322–e331, https://doi.org/10.1093/infdis/jiaf565 31 [18F]Fluorodeoxyglucose Positron Emission Tomography for Diagnosis and Monitoring of Acute Staphylococcus aureus Vascular Graft Infection in a Rat Model [18F]氟脱氧葡萄糖正电子发射断层扫描在诊断和监测大鼠急性金黄色葡萄球菌血管移植物感染中的应用 Emma Faddy and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e332–e341, https://doi.org/10.1093/infdis/jiaf594 32 Safety and Immunogenicity of a Klebsiella pneumoniae Tetravalent Bioconjugate Vaccine (Kleb4V) Administered to Healthy Adults: A First-in-Human Phase I/II Randomized and Controlled Study 健康成年人接种肺炎克雷伯菌四价生物结合疫苗（Kleb4V）的安全性和免疫原性：一项首次人体I/II期随机对照研究 C Alaimo and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e342–e351, https://doi.org/10.1093/infdis/jiaf600 COVID-2019 Disease Pathogenesis（新冠肺炎发病机制） 33 Prevalence of Symptoms Associated With Long COVID Among Adolescents in the United States, Summer 2022 2022年夏季美国青少年中与新冠长期症状相关症状的流行情况 Deja L Edwards and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e352–e362, https://doi.org/10.1093/infdis/jiaf454 34 COVID-19 Vaccine Effectiveness in Patients With Hematologic Malignancies: A Nationwide Cohort Study 血液系统恶性肿瘤患者中COVID-19疫苗的有效性：一项全国性队列研究 Quincy Hofsink and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e363–e372, https://doi.org/10.1093/infdis/jiaf523 35 Safety and Immunogenicity of a Severe Acute Respiratory Syndrome Coronavirus 2 Spike Subunit Vaccine Stabilized in the Prefusion Conformation by a Second-Generation Molecular Clamp and Evaluated in Adults Aged 18–55 Years: A Randomized, Double-Blind, Active Comparator, Phase I Trial 一种由第二代分子夹稳定在融合前构象的严重急性呼吸综合征冠状病毒2型刺突亚单位疫苗在18 - 55岁成年人中的安全性和免疫原性：一项随机、双盲、活性对照、I期试验 Keith J Chappell and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e373–e382, https://doi.org/10.1093/infdis/jiaf568 Viral Disease Pathogenesis（病毒性疾病发病机制） 36 Durability of the Mumps Antibody Response After the Third Dose of MMR Vaccine 接种第三剂麻腮风疫苗后腮腺炎抗体反应的持久性 Sun B Sowers and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e383–e391, https://doi.org/10.1093/infdis/jiaf520 37 Immune Responses to BK Virus in Renal Transplant Recipients Receiving Intravenous Immunoglobulin Treatment 接受静脉注射免疫球蛋白治疗的肾移植受者对BK病毒的免疫反应 Kevin D He and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e392–e403, https://doi.org/10.1093/infdis/jiaf525 38 Epstein-Barr Virus Antibody Response Patterns in Endemic and Nonendemic Cases of Nasopharyngeal Carcinoma 鼻咽癌流行区和非流行区病例中EB病毒抗体反应模式 Ilona Argirion and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e404–e408, https://doi.org/10.1093/infdis/jiaf526 39 Genomic Surveillance and Antigenic Characterization of Respiratory Syncytial Virus (RSV) in Spain During the 2023-2024 Season of Nirsevimab Administration 2023 - 2024年西班牙尼塞韦单抗给药季节呼吸道合胞病毒（RSV）的基因组监测和抗原特征分析 María Iglesias-Caballero and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e409–e418, https://doi.org/10.1093/infdis/jiaf530 40 Establishment of a Cynomolgus Macaque Model for Human Adenovirus Type 55–Induced Respiratory Disease 建立食蟹猴模型用于研究人类55型腺病毒引起的呼吸道疾病 Sang Hwan Seo and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e419–e429, https://doi.org/10.1093/infdis/jiaf542 41 Adenovirus 40 and 41 Antibodies Associated With Protection From Infection in a Bangladeshi Birth Cohort 孟加拉国出生队列中与预防腺病毒40型和41型感染相关的抗体 Jennifer Hendrick and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e430–e440, https://doi.org/10.1093/infdis/jiaf558 42 Natural History of Nipah Virus in Hamsters: Strain, Route, and Sex-Associated Variability Characterized Using Large Datasets to Inform Pre-Clinical Study Design 利用大型数据集研究仓鼠中尼帕病毒的自然史：不同毒株、感染途径和性别的变异性，为临床前研究设计提供依据 Katherine A Davies and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e441–e453, https://doi.org/10.1093/infdis/jiaf549 43 Estimation of Prevention-Effective CAB-LA Concentrations Among Men Who Have Sex With Men (MSM) and Transgender Women (TGW) in HPTN 083 在HPTN 083研究中估算男男性行为者（MSM）和跨性别女性（TGW）中预防有效的长效卡博特韦浓度 Brett Hanscom and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e454–e461, https://doi.org/10.1093/infdis/jiaf561 44 Assessment of Concordant Human Papillomavirus Infection With 9-Valent Vaccine Types Across Anogenital Sites in Young Men 评估年轻男性肛门生殖器部位九价疫苗类型人乳头瘤病毒的一致感染情况 Cara J Broshkevitch and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e462–e470, https://doi.org/10.1093/infdis/jiaf564 Parasites（寄生虫） 45 From Skin to Sequence: Pan-species Detection and Speciation of Leishmania 从皮肤到序列：利什曼原虫的全物种检测与鉴定 Nicholas R Duncan and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e471–e480, https://doi.org/10.1093/infdis/jiaf345 46 A Human Monoclonal Antibody Targeting α-Gal Ameliorates Experimental Cutaneous Leishmaniasis 一种靶向α-半乳糖苷的人单克隆抗体可改善实验性皮肤利什曼病 Hyeseon Cho and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e481–e490, https://doi.org/10.1093/infdis/jiaf350 47 Artemisinin Partial Resistance Mutations in Zanzibar and Tanzania Suggest Regional Spread and African Origins, 2023 2023年桑给巴尔和坦桑尼亚的青蒿素部分耐药突变提示区域传播和非洲起源 Sean V Connelly and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e491–e495, https://doi.org/10.1093/infdis/jiaf431 48 A Multivalent Peptide Vaccine Against Malaria, Targeting Plasmodium Circumsporozoite Protein and Mosquito AgTRIO 一种针对疟疾的多价肽疫苗，靶向疟原虫环子孢子蛋白和蚊子AgTRIO Yu-Min Chuang and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e496–e500, https://doi.org/10.1093/infdis/jiaf432 49 Spontaneous Clearance of Polymerase Chain Reaction–Positive Plasmodium vivax Parasitemia in Northwestern Thailand: An Epidemiological Perspective 泰国西北部聚合酶链反应阳性的恶性疟原虫血症的自发清除：流行病学视角 Pyae Linn Aung and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e501–e509, https://doi.org/10.1093/infdis/jiaf473 50 Gene Editing of a Carcinogenic Liver Fluke Tetraspanin Impairs Parasite Surface Biogenesis and Extracellular Vesicle Uptake by Human Host Cells 对致癌性肝吸虫四跨膜蛋白进行基因编辑，可损害寄生虫表面生物合成以及人宿主细胞对细胞外囊泡的摄取 Sujittra Chaiyadet and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e510–e520, https://doi.org/10.1093/infdis/jiaf466 Antimicrobial Resistance (AMR)（抗菌药物耐药性） 51 Ampicillin/Sulbactam in Combination with Ceftazidime/Avibactam Against Metallo-β-Lactamase-Producing Carbapenem-Resistant Acinetobacter baumannii: A Genomics-Informed Mechanism-based model 氨苄西林/舒巴坦联合头孢他啶/阿维巴坦治疗产金属β-内酰胺酶的碳青霉烯耐药鲍曼不动杆菌：基于基因组学的机制模型 Bhavatharini Arun and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e521–e533, https://doi.org/10.1093/infdis/jiaf567 52 CRISPR-Cas–associated SCCmec Variants in Methicillin-resistant Staphylococcus aureus Evade Rapid Diagnostic Detection 耐甲氧西林金黄色葡萄球菌中与CRISPR-Cas相关的SCCmec变异体可逃避快速诊断检测 Magdalena Podkowik and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e534–e540, https://doi.org/10.1093/infdis/jiaf575 53 Evaluation of Phenotypic and Genotypic Susceptibility Testing Methods for Newer β-lactam/β-lactamase Inhibitor Combinations in Multidrug Resistant Pseudomonas aeruginosa 评估多药耐药铜绿假单胞菌中新型β-内酰胺/β-内酰胺酶抑制剂组合的表型和基因型敏感性检测方法 Clayton W Hall and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e541–e549, https://doi.org/10.1093/infdis/jiaf585 Fungi（真菌） 54 Adrenal Corticosteroids and Increased Intracranial Pressure in Nonimmunocompromised Patients With Cryptococcal Meningitis 非免疫抑制患者隐球菌性脑膜炎的肾上腺皮质类固醇与颅内压升高 John E Bennett and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e550–e552, https://doi.org/10.1093/infdis/jiaf490 55 Corticosteroid Therapy and Long-Term Outcomes of Post-Infectious Inflammatory Syndrome in Non-HIV Immunosuppressed Cryptococcal Meningitis: A Multicenter Case Series 非HIV免疫抑制隐球菌性脑膜炎患者感染后炎性综合征的皮质类固醇治疗和长期预后：一项多中心病例系列研究 Yuya Ito and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e553–e560, https://doi.org/10.1093/infdis/jiaf620 56 Cerebral Venous Thrombosis in Previously Healthy Patients with Cryptococcal Meningitis 既往健康患者隐球菌性脑膜炎并发脑静脉血栓形成 Seher H Anjum and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e561–e569, https://doi.org/10.1093/infdis/jiaf653 57 The Gut as a Source of Infection for Fungal Pathogens: Increased Fecal Candida albicans Precedes Onset of Candida Late-Onset Sepsis in Very Preterm Infants 肠道作为真菌病原体感染的来源：极早产儿白色念珠菌粪便含量增加早于迟发性念珠菌脓毒症发作 Rimke R de Kroon and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e570–e581, https://doi.org/10.1093/infdis/jiaf524 Correspondence（读者来信） 58 Accurate Measurement of Viral Clearance in Early-Phase Antiviral Studies in Coronavirus Disease 2019 2019冠状病毒病早期抗病毒研究中病毒清除的准确测量 Phrutsamon Wongnak and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e582–e584, https://doi.org/10.1093/infdis/jiaf442 59 Evaluating Viral Load Sampling Schemes and Swabbing Methods for Optimal Surrogacy 评估病毒载量采样方案和拭子采集方法以实现最佳替代指标 Allyson Mateja and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e585–e586, https://doi.org/10.1093/infdis/jiaf443 60 Effect of 5FU on paracoccidioidomycosis 5-氟尿嘧啶对副球孢子菌病的影响 David A Stevens The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Page e587, https://doi.org/10.1093/infdis/jiaf508 61 Response to D. Stevens Letter 对D. Stevens信件的回复 Nycolas Preite The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Page e588, https://doi.org/10.1093/infdis/jiaf509 62 Evaluating Clinical Impacts of Accessory Genome Elements: Escherichia coli Type III Secretion System 2 in Escherichia coli and Beyond! 评估附属基因组元件的临床影响：大肠杆菌III型分泌系统2在大肠杆菌及其他细菌中的作用！ Abi Manesh and others The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e589–e590, https://doi.org/10.1093/infdis/jiaf515 63 Alarming Prevalence of Gonococcal Ceftriaxone Resistance in Vietnam—Role of Periodic Presumptive Antimicrobials? 越南淋球菌头孢曲松耐药性的惊人流行率——定期假定使用抗菌药物的作用？ Chris Kenyon The Journal of Infectious Diseases, Volume 233, Issue 2, 15 February 2026, Pages e591–e592, https://doi.org/10.1093/infdis/jiaf553 The Journal of Infectious Diseases. Volume 233 Issue 3 传染病杂志 233卷 3期 https://academic.oup.com/jid/issue/ Editorial（社论） 1 Mechanistic Insights Into Increased Vulnerability to Respiratory Infections in HIV-Exposed Uninfected Infants 未感染婴儿HIV暴露对呼吸道感染易感性增加的机制研究 Cheryl Cohen and Penny Moore The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 417–419, https://doi.org/10.1093/infdis/jiaf494 Viewpoint（观点） 2 Every Body Has Value: Ending Discriminatory Restrictions on Anatomical Donations 每例身体都有其价值：终止对解剖捐赠的歧视性限制 Sara Gianella and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 420–422, https://doi.org/10.1093/infdis/jiaf413 ID Translational Science Update（传染病转化医学最新进展） 3 Syphilis Transmission: Contagion of Bodies and Words 梅毒传播：身体与言语的双重传播 Maurizio Bifulco and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 423–427, https://doi.org/10.1093/infdis/jiaf576 Major Articles and Brief Reports（主要论著与简要报告） HIV/AIDs（人类免疫缺陷病毒/艾滋病） 4 Maternal Inflammation Likely Drives Impaired Immune Responses to Respiratory Syncytial Virus in HIV-Exposed Uninfected Infants 母体炎症可能是导致HIV暴露于未感染婴儿对呼吸道合胞病毒免疫应答受损的原因 Christiana Smith and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 428–439, https://doi.org/10.1093/infdis/jiaf493 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 5 Large Reductions in Invasive Pneumococcal Disease and Related Morbidities Among Children in New Zealand After Change From PCV10 to PCV13 新西兰儿童在从PCV10换用PCV13后，侵袭性肺炎球菌病及相关发病率大幅下降 Andrew Anglemyer and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 440–444, https://doi.org/10.1093/infdis/jiaf587 6 Lack of S100A8 Impairs Lung-Protective Immunity Against Streptococcus pneumoniae 缺乏S100A8会损害针对肺炎链球菌的肺部保护性免疫 Lena Ostermann and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 445–457, https://doi.org/10.1093/infdis/jiaf647 7 Microbial Dominance in Diabetic Foot Osteomyelitis Determined With Nanopore Sequencing Techniques Predicts Positive Response to Surgical Intervention 利用纳米孔测序技术确定糖尿病足骨髓炎中的微生物优势种，可预测对手术干预的积极反应 Brian M Schmidt and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 458–464, https://doi.org/10.1093/infdis/jiaf617 8 Characteristics and Antiadhesion Activity of Chicken Single-Chain Fragment Variable Antibodies Against Helicobacter pylori Adhesin A 针对幽门螺杆菌黏附素A的鸡单链抗体片段的特性及其抗黏附活性 Yanan Gong and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 465–474, https://doi.org/10.1093/infdis/jiaf550 9 Bartonella henselae Subverts Host Cell Apoptosis by Linking Intracellular NOD2 Sensing to an AREG/EGFR Autocrine Survival Loop 汉赛巴尔通体通过将细胞内NOD2感知与AREG/EGFR自分泌生存环联系起来，破坏宿主细胞凋亡 Jun He and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 475–484, https://doi.org/10.1093/infdis/jiaf566 Viral Disease Pathogenesis（病毒性疾病发病机制） 10 Influenza-associated Excess Mortality Associated With Influenza B in Hong Kong, 2014–2023 2014 - 2023年香港地区乙型流感相关的超额死亡率 Jessica Y Wong and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 485–492, https://doi.org/10.1093/infdis/jiaf414 11 Disparate Kinetics of Viable Virus Shedding in Immunocompromised Patients: SARS-CoV-2 Versus Influenza Virus—A Prospective Real-World Cohort Study 免疫功能低下患者中存活病毒脱落动力学差异：新冠病毒与流感病毒——一项前瞻性真实世界队列研究 So Yun Lim and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 493–497, https://doi.org/10.1093/infdis/jiaf479 12 Autoantibodies Against Type I Interferons are a Prominent Feature in SARS-CoV-2 Fatal Disease and Hospitalization 针对I型干扰素的自身抗体是严重急性呼吸综合征冠状病毒2型致命性和住院治疗的显著特征 Rebeca Linhares Abreu Netto and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 498–509, https://doi.org/10.1093/infdis/jiaf514 13 Genetic Landscape of a Cohort of Children With Varicella Zoster Virus Encephalitis, Cerebellitis, and Stroke 水痘带状疱疹病毒脑炎、小脑炎和中风患儿队列的遗传学特征 Franziska Winzig and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 510–520, https://doi.org/10.1093/infdis/jiaf448 14 The Diagnostic Value of Soluble Epstein-Barr Virus BZLF1 Protein in Posttransplant Lymphoproliferative Disease Among Solid Organ and Hematopoietic Cell Transplant Recipients 可溶性爱泼斯坦-巴尔病毒BZLF1蛋白在实体器官和造血细胞移植受者移植后淋巴增殖性疾病中的诊断价值 Neval Ete Wareham and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 521–527, https://doi.org/10.1093/infdis/jiaf477 15 Noninvasive Detection of Occult yet Significant Liver Pathology in Alanine Aminotransferase–Normal Chronic Hepatitis B: A Multicenter Study 丙氨酸氨基转移酶正常的慢性乙型肝炎患者中非侵入性检测隐匿却重要的肝脏病理：一项多中心研究 Xinjie Li and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 528–540, https://doi.org/10.1093/infdis/jiaf554 16 Mesenteric Ischemia and Bacterial Translocation Precipitate the Intoxication Phase of Yellow Fever 肠系膜缺血和细菌移位促使黄热病进入中毒阶段 Mateus V Thomazella and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 541–553, https://doi.org/10.1093/infdis/jiaf483 17 Essential Role of Clathrin and Lipid Rafts in pH-dependent Entry of Chandipura Virus: Independence From Caveolin Pathway 网格蛋白和脂质筏在Chandipura病毒pH依赖性进入过程中的重要作用：独立于小窝蛋白途径 Ritudhwaj Tiwari and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 554–559, https://doi.org/10.1093/infdis/jiaf446 Fungi（真菌） 18 Blood Cultures Contain Populations of Genetically Diverse Candida albicans Strains that May Differ in Echinocandin Tolerance and Fitness 血培养中含有遗传多样的白色念珠菌菌株群体，这些菌株在棘白菌素耐受性和适应性方面可能存在差异 Giuseppe Fleres and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 560–572, https://doi.org/10.1093/infdis/jiaf495 19 Interferon-gamma Production Defects Characterize Immune Responses in Patients With Chronic Pulmonary Aspergillosis 干扰素-γ产生缺陷是慢性肺曲霉病患者免疫应答的特征 Nico A F Janssen and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 573–582, https://doi.org/10.1093/infdis/jiaf596 20 Tumor Necrosis Factor Receptor–Associated Factor 1 Inhibits Macrophage Killing of Sporothrix schenckii by Enhancing Expression and Activity of Inducible Nitric Oxide Synthase 肿瘤坏死因子受体相关因子1通过增强诱导型一氧化氮合酶的表达和活性，抑制巨噬细胞对申克孢子丝菌的杀伤作用 Congcong He and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 583–593, https://doi.org/10.1093/infdis/jiaf646 Global Health（全球健康） 21 Rifampin Exposure in Pregnant and Nonpregnant Women With Tuberculosis in India 印度结核病孕妇和非孕妇的利福平暴露情况 Prakruti S Rao and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 594–597, https://doi.org/10.1093/infdis/jiaf467 22 Evaluating the Impact of Unadjusted Confounding and Study Design on Estimated Pathogen-attributable Diarrhea Incidence Among Children in the MAL-ED Cohort 评估未调整混杂因素和研究设计对MAL-ED队列中儿童病原体归因腹泻发病率估计的影响 Charlotte R Doran and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 598–606, https://doi.org/10.1093/infdis/jiaf531 23 Defining Severe Shigellosis in the Enterics for Global Health Study: A Comparison of Leading Diarrhea Severity Definitions Among Children With Shigella Diarrhea 全球肠道健康研究中对儿童严重志贺氏菌病的定义：志贺氏菌腹泻儿童中主要腹泻严重程度定义的比较 Olivia Lang Schultes and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages 607–617, https://doi.org/10.1093/infdis/jiaf630 Editorial（社论） 24 Evidence for Neuroinvasive Lassa Virus Infection in Pediatric Patients: Initial Findings and Implications 儿科患者神经侵袭性拉沙病毒感染的证据：初步发现及启示 Andrew P Platt and Daniel S Chertow The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e593–e595, https://doi.org/10.1093/infdis/jiaf548 Perspectives（展望） 25 The Emerging Role of Immunothrombosis in the Control and Pathogenesis of Mycobacterium tuberculosis 免疫血栓形成在结核分枝杆菌控制和发病机制中的新兴作用 Seán Donohue and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e596–e599, https://doi.org/10.1093/infdis/jiaf415 ID Translational Science Update（传染病转化医学最新进展） 26 Whole-Exome Sequencing for the Identification of Genetic Factors Implicated in Severe Bacterial Infections: A Systematic Review 全外显子组测序用于鉴定与严重细菌感染相关的遗传因素：一项系统综述 Morgane Gélin and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e600–e610, https://doi.org/10.1093/infdis/jiag006 Major Articles and Brief Reports（主要论著与简要报告） Viral Disease Pathogenesis（病毒性疾病发病机制） 27 Presence of Lassa Virus RNA in Cerebrospinal Fluid Indicating Neuroinvasive Lassa Fever in Pediatric Patients From Edo State, Nigeria 尼日利亚埃多州儿科患者脑脊液中存在拉沙病毒RNA，表明存在神经侵袭性拉沙热 Hannah Caroline Sophie Müller and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e611–e620, https://doi.org/10.1093/infdis/jiaf547 28 Anti-HBs Immune Complex Levels: A Novel Marker of Hepatitis Flare Following Nucleos(t)ide Analog Withdrawal in HBeAg-negative Chronic Hepatitis B 抗-HBs免疫复合物水平：乙型肝炎e抗原阴性慢性乙型肝炎患者核苷（酸）类似物停药后肝炎发作的新型标志物 S J Hume and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e621–e629, https://doi.org/10.1093/infdis/jiaf569 29 Oral Microbiome Diversity Matters on Nucleos(t)ide Analogue Cessation in Chronic Hepatitis B 慢性乙型肝炎患者核苷（酸）类似物停药时口腔微生物组多样性的重要性 Mahin Ghorbani and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e630–e640, https://doi.org/10.1093/infdis/jiaf591 30 A Phase 1 Double-Blinded Trial to Evaluate Safety, Immunogenicity, and Dosing of Measles-Vectored Chikungunya Virus Vaccine (MV-CHIK) in Healthy Adults 一项评估健康成年人接种麻疹载体基孔肯雅病毒疫苗（MV-CHIK）的安全性、免疫原性和剂量的1期双盲试验 Patricia Winokur and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e641–e645, https://doi.org/10.1093/infdis/jiaf571 31 A Test-Negative Design for Immune Correlates Approximates a Traditional Exposure-Proximal Design but Requires Far Fewer Blood Samples 免疫相关因素的检验阴性设计近似于传统的暴露近端设计，但所需血液样本数量要少得多 Dean Follmann and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e646–e650, https://doi.org/10.1093/infdis/jiaf572 32 Comparison of Healthcare Resource Utilization and Disease Outcomes in Adults Hospitalized with Human Metapneumovirus and Respiratory Syncytial Virus 人偏肺病毒和呼吸道合胞病毒感染住院成人患者的医疗资源利用情况和疾病预后比较 Emily Rayens and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e651–e661, https://doi.org/10.1093/infdis/jiaf597 33 Avian Influenza Virus A(H5N1) Genotype D1.1 Is Better Adapted to Human Nasal and Airway Organoids Than Genotype B3.13 禽流感病毒A(H5N1) D1.1基因型比B3.13基因型更适应人体鼻腔和气道类器官 Xiaojuan Zhang and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e662–e666, https://doi.org/10.1093/infdis/jiaf598 34 The Impact of Corticosteroid Therapy on Patients With West Nile Virus: A Retrospective Cohort Study 皮质类固醇治疗对西尼罗河病毒患者的影响：一项回顾性队列研究 Itamar Poran and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e667–e673, https://doi.org/10.1093/infdis/jiaf601 35 Serological Survey in African Nonhuman Primate Species in Cameroon and the Democratic Republic of the Congo Reveals Low Overall Seroprevalence to Mpox Virus 对喀麦隆和刚果民主共和国非洲非人灵长类物种的血清学调查显示，猴痘病毒总体血清阳性率较低 Neraide Biai and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e674–e686, https://doi.org/10.1093/infdis/jiaf602 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 36 Manufacture of Clostridioides difficile Spores for Experimental Infection of Human Volunteers 用于人体志愿者实验性感染的艰难梭菌孢子制备 Annefleur D O Hensen and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e687–e695, https://doi.org/10.1093/infdis/jiaf612 37 Digital Anorectal Examination to Self-detect Primary Syphilis: A Prospective Cohort Study 数字肛门直肠检查用于自我检测原发性梅毒：一项前瞻性队列研究 Julien Tran and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e696–e705, https://doi.org/10.1093/infdis/jiaf628 38 Higher Promoter Methylation of the Ubiquitin-Associated and SH3 Domain Containing A (UBASH3A) Gene Is Associated With T-Lymphocyte Ontogeny and Reduced Susceptibility to Early-Onset Sepsis 泛素相关和SH3结构域含A（UBASH3A）基因启动子高甲基化与T淋巴细胞发生及早发性脓毒症易感性降低相关 Ziyi Wang and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e706–e711, https://doi.org/10.1093/infdis/jiaf636 39 Efficacies of Sequenced Monotherapies of Mycobacterium avium Lung Infection in Mouse 小鼠肺鸟分枝杆菌感染序贯单一疗法的疗效 Ruth A Howe and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e712–e720, https://doi.org/10.1093/infdis/jiaf640 40 The Landscape and Regulatory Determinants of A-to-I RNA Editing in Escherichia coli and Pseudomonas aeruginosa Isolated From Patients With Urinary Tract and Ear Infections 从尿路感染和耳部感染患者中分离出的大肠杆菌和铜绿假单胞菌中A-to-I RNA编码的格局及调控决定因素 Eyal Elias and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e721–e730, https://doi.org/10.1093/infdis/jiaf645 Parasites（寄生虫） 41 Efficacy of Praziquantel for Treatment of Plasmodium falciparum Infection in Asymptomatic Gabonese Adults: A Double-Blind Placebo-Controlled Randomized Trial 双盲安慰剂对照随机试验评估吡喹酮治疗加蓬无症状成人恶性疟原虫感染的疗效 Johannes Mischlinger and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e731–e739, https://doi.org/10.1093/infdis/jiaf544 42 Chronic Malaria Is Associated With Trauma-related Splenic Rupture Requiring Splenectomy 慢性疟疾与创伤性脾破裂相关，需行脾切除术 Putu A I Shanti and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e740–e744, https://doi.org/10.1093/infdis/jiaf629 43 Extreme Genetic Diversity and Signatures of Balancing Selection in Plasmodium vivax Blood-Stage Antigens 间日疟原虫血液阶段抗原具有极高的遗传多样性和平衡选择的特征 Alison Paolo N Bareng and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e745–e755, https://doi.org/10.1093/infdis/jiaf539 44 How Duffy Blood Group (FY) Polymorphism and Age Modulate Vivax Malaria Risk at the Community Level: A Population-based Retrospective Cohort Study in the Amazon 社区层面杜菲血型（FY）多态性和年龄如何调节间日疟风险：亚马逊地区一项基于人群的回顾性队列研究 Carlos A Prete and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e756–e765, https://doi.org/10.1093/infdis/jiaf562 45 New Viability Assays for Acanthamoeba castellanii Trophozoites and Cysts Allow Rapid Assessment of Drug Activity 卡氏棘阿米巴滋养体和包囊新的活性检测方法可快速评估药物活性 Carrie A Flynn and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e766–e776, https://doi.org/10.1093/infdis/jiaf599 Global Health（全球健康） 46 Stunting Increases Influenza Virus Shedding Duration in Preschool/School-Aged Children 发育迟缓会增加学龄前/学龄儿童流感病毒脱落持续时间 Mia Q Zhu and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e777–e781, https://doi.org/10.1093/infdis/jiaf641 47 False-positive Malaria Rapid Diagnostic Tests are Prevalent Among Children Under 5 Years of Age in Uganda 乌干达5岁以下儿童疟疾快速诊断试验假阳性率较高 Caitlin A Cassidy and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e782–e790, https://doi.org/10.1093/infdis/jiaf604 48 Comparative Analysis of Flight Volume Effects on COVID-19 and Influenza Transmission Across Variable Control Intensities, 2019–2024 2019 - 2024年不同防控强度下航班量对新冠肺炎和流感传播影响的比较分析 Yanfang Xu and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e791–e801, https://doi.org/10.1093/infdis/jiaf545 49 High Seropositivity to rK39 and Capture of Leishmania-Infected Sand Flies in Bihar and Jharkhand Emphasize the Need for Post-Elimination Surveillance of Visceral Leishmaniasis in India 比哈尔邦和贾坎德邦rK39血清阳性率高且捕获到感染利什曼原虫的白蛉，强调印度内脏利什曼病消除后需加强监测 Eva Iniguez and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e802–e811, https://doi.org/10.1093/infdis/jiaf543 Microbiome（微生物组） 50 The Gut Microbiome and Butyrate Differentiate Clostridioides difficile Colonization and Infection in Children 肠道微生物组和丁酸盐可区分儿童艰难梭菌定植和感染 Maribeth R Nicholson and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e812–e822, https://doi.org/10.1093/infdis/jiaf631 51 Gut Microbiota Predicts the Risk of Future COVID-19 Hospitalization and Mortality: Insights From the Population-Based HELIUS Study 肠道微生物群可预测未来新冠肺炎住院和死亡风险：来自基于人群的HELIUS研究的见解 Robert F J Kullberg and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e823–e827, https://doi.org/10.1093/infdis/jiaf541 52 Douching Is Associated With Dysregulated Rectal Mucosal Immunity in Sexual Minority Men 灌洗与性少数男性直肠黏膜免疫失调相关 Courtney A Broedlow and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e828–e838, https://doi.org/10.1093/infdis/jiaf577 Correspondence（读者来信） 53 Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Pneumonia Hospitalization Among Medicare Beneficiaries Aged ≥65 in Long-Term Care 13价肺炎球菌结合疫苗对长期护理机构中≥65岁医疗保险受益人肺炎住院的预防效果 Wenwen Zhao and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Page e839, https://doi.org/10.1093/infdis/jiaf581 54 Letter to the Editor in Response to Zhao et al 致编辑的信（回应赵等人） Lindsay Zielinski and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e840–e841, https://doi.org/10.1093/infdis/jiaf582 55 Fishborne Trematodiases in the United States: A Blind Spot in U.S. Emerging Infectious Disease Preparedness 美国鱼源性吸虫病：美国新兴传染病防范中的盲点 Nathkapach K Rattanapitoon and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e842–e843, https://doi.org/10.1093/infdis/jiaf588 56 Comment on “A Review of Aedes aegypti Control in Peru: Approaches and Lessons Learned” 对“秘鲁伊蚊控制回顾：方法与经验教训”的评论 Carmen Thompson Perea and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e844–e845, https://doi.org/10.1093/infdis/jiaf589 57 Balancing Pharmacokinetic Targets and Lymphocyte Declines with Once-Monthly Oral Islatravir for PrEP 平衡药代动力学目标和淋巴细胞减少情况，每月一次口服艾斯拉特韦用于暴露前预防 Anxin Wen The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e846–e847, https://doi.org/10.1093/infdis/jiaf618 58 Polio-Free, Not Risk-Free: Wastewater as Early Warning 无脊髓灰质炎，但并非无风险：废水作为早期预警 Francesco Branda and others The Journal of Infectious Diseases, Volume 233, Issue 3, 15 March 2026, Pages e848–e849, https://doi.org/10.1093/infdis/jiaf643 The Journal of Infectious Diseases. Volume 233 Issue Supplement_1 传染病杂志 233卷 增刊1期 https://academic.oup.com/jid/issue/233/Supplement_1 SUPPLEMENT（增刊） Molecular Epidemiology of β-Lactam Resistance in Gram-negative Bacteria in China 中国革兰氏阴性菌β-内酰胺酶类抗生素耐药性的分子流行病学 Supplement Articles（增补论著） 1 Aztreonam-Avibactam Resistance Due to Synergistic Interplay of ampC-Related Mutations in Carbapenem-Resistant Enterobacter spp 碳青霉烯耐药肠杆菌属中因ampC相关突变的协同作用导致的氨曲南-阿维巴坦耐药 Yang Zeng and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S1–S9, https://doi.org/10.1093/infdis/jiaf384 2 Molecular Mechanisms of β-Lactam Resistance and Its Contribution to Multidrug Resistance in Helicobacter pylori 幽门螺杆菌β-内酰胺酶类抗生素耐药的分子机制及其对多重耐药的影响 Jun Zhou and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S10–S20, https://doi.org/10.1093/infdis/jiaf385 3 Molecular Epidemiology and Persistence of Multidrug-Resistant Acinetobacter baumannii in Zhejiang, China (2015–2020): Insights Into Resistance, Virulence, and Transmission Dynamics 2015 - 2020年中国浙江地区多重耐药鲍曼不动杆菌的分子流行病学及持久性：对耐药性、毒力和传播动态的见解 Yisha Zhang and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S21–S30, https://doi.org/10.1093/infdis/jiaf425 4 Clinical Outcomes in Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae Infection: A Cohort Study 高毒力碳青霉烯耐药肺炎克雷伯菌感染的临床预后：一项队列研究 Ya Hu and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S31–S37, https://doi.org/10.1093/infdis/jiaf460 5 Reduced Susceptibility to Cefepime–Taniborbactam in Carbapenem-Resistant Klebsiella pneumoniae Attributed to Penicillin-Binding Protein 3 Modifications 碳青霉烯耐药肺炎克雷伯菌中因青霉素结合蛋白3修饰导致对头孢吡肟-他尼硼巴坦敏感性降低 Baofang Zhang and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S38–S46, https://doi.org/10.1093/infdis/jiaf463 6 Isolation of Lytic Bacteriophages Against Carbapenem-Resistant Klebsiella pneumoniae of Capsular Type KL64 From Water Collected at Multiple Sites Across China 从中国多个地点采集的水样中分离出针对荚膜型KL64碳青霉烯耐药肺炎克雷伯菌的溶菌性噬菌体 Juan Li and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S47–S55, https://doi.org/10.1093/infdis/jiaf607 7 Clinical and Molecular Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Causing Bloodstream Infection in a Chinese Teaching Hospital 中国某教学医院引起血流感染的碳青霉烯耐药肺炎克雷伯菌的临床和分子特征 Quanfeng Liao and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S56–S63, https://doi.org/10.1093/infdis/jiaf613 8 OmpK35 and OmpK36 Deficiencies Driving High-level Carbapenem Resistance in ST11 Klebsiella Pneumoniae OmpK35和OmpK36缺失导致ST11型肺炎克雷伯菌高水平碳青霉烯耐药 Jiayuan Qin and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S64–S71, https://doi.org/10.1093/infdis/jiaf621 9 Carbapenem-Resistant Klebsiella pneumoniae of Sequence Type 11: A Scoping Review 序列型11的碳青霉烯耐药肺炎克雷伯菌：一项范围综述 Yongqiang Yang and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S72–S80, https://doi.org/10.1093/infdis/jiaf635 10 Emergence of Carbapenem-Resistant Escherichia coli Coharboring blaCTX-M-199 and Penicillin-Binding Protein 3 Insertion Conferring Increased Aztreonam/Avibactam Resistance in South China 中国南方出现携带blaCTX-M-199且青霉素结合蛋白3插入导致氨曲南/阿维巴坦耐药性增强的碳青霉烯耐药大肠埃希菌 Jiong Wang and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S81–S91, https://doi.org/10.1093/infdis/jiag025 11 Challenges and Strategies in Managing β-Lactam–Resistant Pseudomonas aeruginosa in China 中国应对β-内酰胺酶类抗生素耐药的铜绿假单胞菌所面临的挑战和策略 Yue Li and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S92–S103, https://doi.org/10.1093/infdis/jiag033 12 New Delhi Metallo-β-Lactamase Carbapenem-Resistant Klebsiella pneumoniae in Neonates: A Genome-Based Surveillance Study 新生儿中新德里金属β-内酰胺酶碳青霉烯耐药肺炎克雷伯菌：一项基于基因组的监测研究 Liting Liang and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S104–S112, https://doi.org/10.1093/infdis/jiag034 13 Trends of Carbapenem-Resistant Gram-negative Bacteria in China: A Surveillance Study Between 2015 and 2024 2015 - 2024年中国碳青霉烯耐药革兰氏阴性菌的趋势：一项监测研究 Yan Guo and others The Journal of Infectious Diseases, Volume 233, Issue Supplement_1, 15 March 2026, Pages S113–S117, https://doi.org/10.1093/infdis/jiag083 The Journal of Infectious Diseases. Volume 233 Issue 4 传染病杂志 233卷 4期 https://academic.oup.com/jid/issue/ Editorial（社论） 1 The Editors' Update: JID Continues to Evolve 社论更新：《传染病杂志》持续发展 Cornelius J (Neil) Clancy and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 619–620, https://doi.org/10.1093/infdis/jiag159 2 Protocols for Randomized Controlled Trials: Advancing Transparency in Infectious Diseases  随机对照试验方案：提高传染病研究的透明度 Jean-Jacques Parienti and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Page 621, https://doi.org/10.1093/infdis/jiag134 3 Dissecting the Impact of the Gut Microbiome on HIV Reservoir Dynamics 剖析肠道微生物组对HIV储存库动态的影响 Christopher M Basting and Nichole R Klatt The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 622–624, https://doi.org/10.1093/infdis/jiaf560 Viewpoint（观点） 4 Doxycycline Post-exposure Prophylaxis and Off-target Antimicrobial Resistance: Potential Amplification Within Sexual Networks 多西环素暴露后预防用药与非靶向抗菌药物耐药性：性网络内潜在的耐药性放大 Manon Roberts and Peter Davis The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 625–627, https://doi.org/10.1093/infdis/jiaf439 5 Clearing the Air: Rethinking Airway Infection With CFTR Modulators 清除迷雾：重新思考囊性纤维化跨膜转导调节因子调节剂治疗下的气道感染 Edith T Zemanick and Ranjani Somayaji The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 628–630, https://doi.org/10.1093/infdis/jiaf625 Invited ID Translational Science Update（特邀传染病转化医学更新） 6 Microbiota, Mucus, and Modulators: Cystic Fibrosis Infection Pathogenesis in the Cystic Fibrosis Transmembrane Conductance Regulator Modulator Era 微生物群、黏液与调节剂：囊性纤维化跨膜转导调节因子调节剂时代囊性纤维化感染的发病机制 Christina S Thornton and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 631–639, https://doi.org/10.1093/infdis/jiaf626 Major Articles and Brief Reports（论著与简报） HIV/AIDs（人类免疫缺陷病毒/艾滋病） 7 HIV Reservoir Dynamics and Bacteriome Composition Along the Gut Axis 肠道轴上HIV储存库动态与细菌群组成 Mattia Trunfio and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 640–651, https://doi.org/10.1093/infdis/jiaf546 8 Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models 急性和慢性人类免疫缺陷病毒感染中线粒体DNA片段动态：来自人类和非人类灵长类动物模型的见解 Jing Sun and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 652–663, https://doi.org/10.1093/infdis/jiag014 9 Multiancestry Genome-Wide Association Study Identifies Variants in a Zinc Finger Gene Cluster as Novel Regulators of HIV Control 多祖先全基因组关联研究确定锌指基因簇中的变异体作为HIV控制的新型调节因子 Abraham Awada and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 664–673, https://doi.org/10.1093/infdis/jiag072 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 10 Respiratory Syncytial Virus–Mediated Gas6/Axl Axis Induces Hyporesponsive Macrophages to Promote Pneumococcal Proliferation in the Nasopharynx 呼吸道合胞病毒介导的Gas6/Axl轴诱导巨噬细胞低反应性以促进鼻咽部肺炎链球菌增殖 Saki Ishikawa and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 674–684, https://doi.org/10.1093/infdis/jiag004 11 Variable Staphylothrombin Activity in Staphylococcus aureus Bloodstream Infections 金黄色葡萄球菌血流感染中可变的葡萄球菌凝血酶活性 Gregory L Damhorst and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 685–695, https://doi.org/10.1093/infdis/jiag012 12 TLR4–MyD88–NF-κB Signaling in the Airway Epithelium Promotes Acinetobacter baumannii Clearance 气道上皮细胞中的TLR4-MyD88-NF-κB信号通路促进鲍曼不动杆菌的清除 Jisun Kim and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 696–705, https://doi.org/10.1093/infdis/jiag061 Viral Disease Pathogenesis（病毒性疾病发病机制） 13 Ganciclovir Dosing in Premature Infants Receiving Treatment for Congenital Cytomegalovirus Infection: Results of a Prospective Pharmacokinetic Study 先天性巨细胞病毒感染接受治疗的早产儿更昔洛韦剂量：一项前瞻性药代动力学研究结果 Edward P Acosta and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 706–713, https://doi.org/10.1093/infdis/jiaf528 14 National- and State-level SARS-CoV-2 Immunity Trends From January 2020 to December 2023: a Mathematical Modeling Analysis 2020年1月至2023年12月国家及州级SARS-CoV-2免疫趋势：一项数学建模分析 Fayette Klaassen and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 714–724, https://doi.org/10.1093/infdis/jiaf532 15 Risk- and Response-Adapted Treatment in Pediatric Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis 儿童EB病毒相关噬血细胞性淋巴组织细胞增生症的风险和反应适应性治疗 Jing Miao and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 725–734, https://doi.org/10.1093/infdis/jiaf556 16 IPVS Consensus Statement on The Natural History of Cervical Human Papillomavirus Infection 国际乳头瘤病毒学会关于宫颈人乳头瘤病毒感染自然史的共识声明 Marc D Ryser and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 735–744, https://doi.org/10.1093/infdis/jiaf574 17 Long Non-Coding RNA NEAT1 Inhibits Enterovirus 71 Replication by Enhancing IFN-β Transcription Through DDX60 Signaling: Pathological Insights and Clinical Implications 长链非编码RNA NEAT1通过DDX60信号增强IFN-β转录抑制肠道病毒71型复制：病理学见解与临床意义 Dong Li and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 745–757, https://doi.org/10.1093/infdis/jiaf578 18 A Threshold in Anti–EBNA-1 Antibody Titers Distinguishes Salivary EBV Shedders From Nonshedders 抗EBNA-1抗体滴度的阈值可区分唾液EB病毒脱落者与非脱落者 João Vitor Mahler and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 758–762, https://doi.org/10.1093/infdis/jiag010 Tuberculosis（结核病） 19 Tuberculosis Disease Prevalence Among People Who Smoke Illicit Drugs: A Respondent- Driven Sampling Study in the Western Cape, South Africa 南非西开普省使用受访者驱动抽样法研究吸食非法毒品者中结核病的患病率 Samantha Malatesta and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 763–772, https://doi.org/10.1093/infdis/jiaf481 20 Childhood Tuberculosis and Risk of Frailty in Later Life: Evidence From a Nationally Representative Study in Brazil 巴西一项全国代表性研究显示儿童期结核病与晚年衰弱风险的关系 Evelyn Lepka de Lima and Márlon Juliano Romero Aliberti The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 773–776, https://doi.org/10.1093/infdis/jiaf563 21 A Monovalent SMAC Mimetic as a Potential Host-Directed Therapy for Tuberculosis 单价SMAC模拟物作为结核病潜在宿主导向疗法 Jiahong Ji and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 777–786, https://doi.org/10.1093/infdis/jiag031 22 Cerebrospinal Fluid Hypo-inflammation Drives Mortality in HIV-Associated Tuberculous Meningitis 脑脊液低炎症反应是HIV相关结核性脑膜炎死亡的原因 Anna L Wilt and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages 787–798, https://doi.org/10.1093/infdis/jiag032 Editorial（社论） 23 Guiding Lines: Practical and Accessible Approaches for Analyzing Serological Data for Infectious Disease Surveillance 指导方针：用于传染病监测的血清学数据分析的实用且易获取的方法 Laura C Steinhardt The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e850–e852, https://doi.org/10.1093/infdis/jiag054 Perspectives（观点） 24 Commensal Bacteria: An Under-recognized Cause of Pneumonia 共生菌：一种被忽视的肺炎病因 Daniel M Musher and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e853–e856, https://doi.org/10.1093/infdis/jiag053 25 The Role of Antiviral Treatment of Influenza in Reducing Hospitalizations and Other Severe Outcomes: A Need for More Evidence 抗病毒治疗流感在减少住院和其他严重结局方面的作用：需要更多证据 Mark W Tenforde and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e857–e861, https://doi.org/10.1093/infdis/jiaf573 Major Articles and Brief Reports（论著与简报） Special Report（专题报告） 26 Whose Line Is it Anyway? Defining Seropositivity Cutoffs for Infectious Disease Surveillance  究竟以谁为准？确定传染病监测血清阳性临界值 Michael T White and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e862–e871, https://doi.org/10.1093/infdis/jiaf537 Parasites（寄生虫） 27 Quantifying the Role of Importation on Sustained Malaria Transmission in a Low-to-Moderate Burden Region of Southwest Uganda  量化输入在维持乌干达西南部低至中度负担地区疟疾持续传播中的作用 Adrienne Epstein and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e872–e881, https://doi.org/10.1093/infdis/jiag008 28 Antibody-Dependent Neutrophil Phagocytosis of Plasmodium falciparum–Infected Erythrocytes Is Mediated by FcγRIIa  抗体依赖的中性粒细胞吞噬恶性疟原虫感染的红细胞由FcγRIIa介导 Maria Saeed and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e882–e890, https://doi.org/10.1093/infdis/jiag071 29 Comparison of CD4 T-Cell Response in Plasmodium falciparum and vivax Malaria  恶性疟原虫和间日疟原虫疟疾中CD4 T细胞反应的比较 Mayimuna Nalubega and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e891–e901, https://doi.org/10.1093/infdis/jiag115 HIV/AIDs（人类免疫缺陷病毒/艾滋病） 30 Persistent Increased Plasmacytoid Dendritic Cells and Inflammation in People With HIV Years After Tuberculosis  结核病治愈数年后，HIV感染者体内浆细胞样树突状细胞持续增多且炎症反应持续存在 Maureen Ward and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e902–e912, https://doi.org/10.1093/infdis/jiaf499 31 Neuroaxonal Injury in Acute HIV Infection and Following Immediate Antiretroviral Therapy  急性HIV感染期及立即接受抗逆转录病毒治疗后出现的神经轴突损伤 Phillip Chan and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e913–e922, https://doi.org/10.1093/infdis/jiaf583 32 Weekly Oral Prophylaxis With MK-8527 Protects Rhesus Macaques From Intrarectal Challenge With Simian–Human Immunodeficiency Virus  每周口服MK-8527进行预防可保护恒河猴免受猴-人免疫缺陷病毒的直肠攻击 Tracy L Diamond and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e923–e931, https://doi.org/10.1093/infdis/jiaf610 33 Partial Post-exposure Protection by Topical Inserts Containing Tenofovir Alafenamide Fumarate/Elvitegravir in a Macaque Model of Rectal Simian HIV (SHIV) Infection 在猕猴直肠猴免疫缺陷病毒（SHIV）感染模型中，含富马酸替诺福韦艾拉酚胺/埃维替韦的局部插入物提供部分暴露后保护 Natalia Makarova and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e932–e936, https://doi.org/10.1093/infdis/jiaf611 34 Human Immunodeficiency Virus–Associated Proteomic Signature of Myocardial Fibrosis and Incident Heart Failure  人类免疫缺陷病毒相关心肌纤维化和偶发心力衰竭的蛋白质组学特征 Tess E Peterson and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e937–e947, https://doi.org/10.1093/infdis/jiag013 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 35 Treatment of Pseudomonas by Removal of Cloaking Antibodies: Is Common Polysaccharide Antigen a Factor?  通过去除伪装抗体治疗铜绿假单胞菌感染：常见多糖抗原是否是一个因素？ Joshua N Monteith and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e948–e956, https://doi.org/10.1093/infdis/jiag002 36 High Prevalence and Genotypic Diversity of Persistent Chlamydia Trachomatis Infections Among South African Adolescent Girls and Young Women: A Tale of Two Cities  南非少女和年轻女性中持续性沙眼衣原体感染的患病率高且基因型多样：两个城市的对比情况 Smritee Dabee and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e957–e962, https://doi.org/10.1093/infdis/jiag023 37 The Effect of Pertussis Vaccination During Pregnancy on the Binding Epitopes and Avidity of Anti–Pertussis Toxin Immunoglobulin G Antibodies in Infants and Their Mothers  孕期接种百日咳疫苗对婴儿及其母亲体内抗百日咳毒素免疫球蛋白G抗体的结合表位和亲和力的影响 Aapo Knuutila and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e963–e972, https://doi.org/10.1093/infdis/jiag048 Tuberculosis（结核病） 38 Accuracy of the Phenotypic 1G Test to Detect Mycobacterium tuberculosis and Drug Resistance From Sputa in the US-Mexico Border  表型1G试验检测美国-墨西哥边境痰液中结核分枝杆菌及耐药性的准确性 Mia Aguirre and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e973–e980, https://doi.org/10.1093/infdis/jiaf638 39 Mycobacterium tuberculosis–Specific CFP-10/ESAT-6 CD4 and CD8 T-Cell Non-IFN-γ+ Responses Are Common in Young Kenyan Children Despite Low Reported Tuberculosis Exposure  尽管报告的结核病暴露率较低，但肯尼亚幼儿中仍普遍存在结核分枝杆菌特异性CFP-10/ESAT-6 CD4和CD8 T细胞非γ干扰素阳性反应 Sylvia M LaCourse and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e981–e989, https://doi.org/10.1093/infdis/jiag039 40 Modeling the Impact of Case Finding for Tuberculosis: The Role of Infection Dynamics  结核病病例发现的影响建模：感染动态的作用 Theresa S Ryckman and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e990–e998, https://doi.org/10.1093/infdis/jiag050 41 Population Pharmacokinetic Modeling of Standard- and High-Dose Rifampicin for Tuberculosis Preventive Therapy in the 2R2 Randomized Controlled Trial  2R2随机对照试验中用于结核病预防治疗的标准剂量和高剂量利福平的群体药代动力学建模 Fajri Gafar and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e999–e1010, https://doi.org/10.1093/infdis/jiag052 Viruses（病毒） 42 Improved Immune Response Against Influenza A Viruses With Receipt of a Recombinant Influenza Vaccine in Healthcare Personnel With Prior Low Antibody Response to Egg-Based Influenza Vaccines, Israel, 2019–2020 2019-2020年，以色列既往对基于鸡蛋的流感疫苗抗体反应低的医护人员接种重组流感疫苗后，对甲型流感病毒的免疫反应有所改善 Kelsey M Sumner and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1011–e1021, https://doi.org/10.1093/infdis/jiaf605 43 Antineuraminidase Antibody Responses in Older Adults After Consecutive Vaccinations With Enhanced Influenza Vaccines: A Randomized Controlled Trial  老年人连续接种强化流感疫苗后抗神经氨酸酶抗体反应：一项随机对照试验 Pavithra Daulagala and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1022–e1030, https://doi.org/10.1093/infdis/jiaf616 44 The Pandemic Respiratory Virus Epidemiological Surveillance Trial-A Self-swab Surveillance System for Respiratory Viruses Nested Within FluTracking  大流行性呼吸道病毒流行病学监测试验——嵌入FluTracking的呼吸道病毒自我拭子监测系统 Camille Esneau and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1031–e1039, https://doi.org/10.1093/infdis/jiaf632 45 Intracellular Ganciclovir Triphosphate Concentrations in Children With Congenital Cytomegalovirus Infection  先天性巨细胞病毒感染患儿体内更昔洛韦三磷酸的细胞内浓度 Brent Lindquist-Kleissler and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1040–e1045, https://doi.org/10.1093/infdis/jiaf633 46 Hepatitis E Virus Infection in Patients With Chronic Liver Diseases: A Latin American Multicenter Study  拉丁美洲多中心研究：慢性肝病患者中的戊型肝炎病毒感染情况 Anabella Clara Fantilli and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1046–e1055, https://doi.org/10.1093/infdis/jiaf615 47 In Vivo Risk Assessment of Yellow Fever Virus Transmission Through Breastfeeding, and Mechanistic Insights  母乳喂养传播黄热病病毒的体内风险评估及机制研究 Jeanne Pascard and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1056–e1068, https://doi.org/10.1093/infdis/jiaf637 Letters to the Editor（致编辑的信） 48 Re: Estimating the Early Transmission Inhibition of New Treatment Regimens for Drug-Resistant Tuberculosis 回复：估算耐药结核病新治疗方案对早期传播的抑制作用 Tom A Yates and David A Barr The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1069–e1070, https://doi.org/10.1093/infdis/jiaf655 49 Reply to Yates and Barr 回复耶茨和巴尔 Ruvandhi R Nathavitharana and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1071–e1072, https://doi.org/10.1093/infdis/jiaf656 50 How “Enhanced” Are Enhanced Influenza Vaccines for Neuraminidase? Antigen Content and Baseline Immunity Revisited 强化流感疫苗对神经氨酸酶的“强化”程度如何？重新审视抗原含量和基线免疫力 Xiaowei Zhang The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1073–e1074, https://doi.org/10.1093/infdis/jiag042 51 Response to Letter to the Editor Regarding the Immunogenicity of Enhanced Influenza Vaccines in Inducing Neuraminidase Inhibition Antibodies 回复致编辑的关于“强化流感疫苗诱导神经氨酸酶抑制抗体免疫原性”的信 Pavithra Daulagala and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1075–e1076, https://doi.org/10.1093/infdis/jiag043 52 Comment on B-Cell Subset Representation Predicts SARS-CoV-2 Vaccine Response in Solid Organ Transplant Recipients 关于“B细胞亚群表征预测实体器官移植受者对SARS-CoV-2疫苗反应”的评论 Pınar Belviranlı Keskin The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Page e1077, https://doi.org/10.1093/infdis/jiag055 53 Response to Dr Belviranli Keskin's Comments 回复贝尔维兰利·凯斯金的评论 James J Knox and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Page e1078, https://doi.org/10.1093/infdis/jiag056 54 Beyond Antibodies: Influenza Vaccine Induced T-Cell Response in Hematological Malignancy— Commentary on Insights From Hall et al 超越抗体：流感疫苗在血液系统恶性肿瘤患者中诱导的T细胞反应——对霍尔等人见解的评论 Katja M Sauer and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1079–e1080, https://doi.org/10.1093/infdis/jiag079 55 Advancing Understanding of Viral Interference: Insights From Rhinovirus–SARS-CoV-2 Cross-protection and Immunologic Perspectives 加深对病毒干扰的理解：来自鼻病毒-SARS-CoV-2交叉保护和免疫学视角的见解 Weikai Dong and others The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1081–e1082, https://doi.org/10.1093/infdis/jiag080 56 When PD-1 Meets Plaque: Making CD8 Senescence Signals Clinically Actionable in Treated HIV 当PD-1遇上斑块：使治疗后的HIV感染者中CD8细胞衰老信号具有临床可操作性 Xiaowei Zhang The Journal of Infectious Diseases, Volume 233, Issue 4, 15 April 2026, Pages e1083–e1084, https://doi.org/10.1093/infdis/jiag081 The Journal of Infectious Diseases. Volume 233 Issue 5 传染病杂志 233卷 5期 https://academic.oup.com/jid/issue/ Editorial（社论） 1 Beyond Transplantation: Cytomegalovirus Viremia as a Therapeutic Target in Non-Cytomegalovirus Syndromes 超越移植：巨细胞病毒血症作为非巨细胞病毒综合征的治疗靶点 Ghady Haidar The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 799–801, https://doi.org/10.1093/infdis/jiaf648 2 When Time Is of the Essence: Hepatitis C Virus RNA Point-of-Care Testing in 15Minutes Becomes a Reality 当时间至关重要：15分钟内完成丙型肝炎病毒RNA即时检测成为现实 Tanya L Applegate and Jason Grebely The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 802–805, https://doi.org/10.1093/infdis/jiaf652 Trainee’s Corner（实习生专栏） 3 The Day I Was Told I Wasn’t Doing Science—And Why I’m Grateful for It 被告知我没有在做科学的那一天——以及我为何对此心怀感激 Sara Gianella The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 806–808, https://doi.org/10.1093/infdis/jiaf614 JID Viewpoint（《传染病杂志》观点） 4 Restoring TB-specific Immunity in Early HIV Infection—the Dual Promise of Early Antiretroviral and TB Preventive Treatment 在HIV感染早期恢复结核特异性免疫——早期抗逆转录病毒治疗与结核预防性治疗的双重前景 Patrick K Moonan and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 809–811, https://doi.org/10.1093/infdis/jiaf518 Major Articles and Brief Reports（主要论著与简报） Viral Disease Pathogenesis（病毒性疾病发病机制） 5 Cytomegalovirus DNAemia in Hospitalized Adults With SARS-CoV-2 Infection Requiring Supplemental Oxygen: Virologic and Clinical Characteristics and Association With Outcomes  需要补充氧疗的住院成人SARS-CoV-2感染患者中的巨细胞病毒DNA血症：病毒学与临床特征及其与预后的关系 Michael Boeckh and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 812–822, https://doi.org/10.1093/infdis/jiaf649 6 Development of a Rapid Automated Point-of-Care Test for Hepatitis C Viral RNA on the DASH Rapid Polymerase Chain Reaction System  基于DASH快速聚合酶链反应系统的丙型肝炎病毒RNA快速自动化即时检测的开发 Jennifer L Reed and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 823–830, https://doi.org/10.1093/infdis/jiaf608 7 Serum Markers of Fibroinflammatory Activity PRO-C3 and CPa9-HNE Are Associated with Liver-Related Outcomes in Patients with Chronic Hepatitis C 纤维炎症活动血清标志物PRO-C3和CPa9-HNE与慢性丙型肝炎患者肝脏相关预后有关 Emilie Toft Skovgaard and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 831–839, https://doi.org/10.1093/infdis/jiaf552 8 A Rapid Assay for Hepatitis C Virus RNA Detection Using Reverse-Transcription Loop-Mediated Isothermal Amplification–Coupled CRISPR-Cas12b–Based Strategy 基于逆转录环介导等温扩增联合CRISPR-Cas12b策略的丙型肝炎病毒RNA快速检测方法 Avisha Chowdhury and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 840–847, https://doi.org/10.1093/infdis/jiaf609 9 Maternal-Fetal Letermovir Exposure In Vivo and Physiologically Based Pharmacokinetic Modeling: A Rationale for Congenital Cytomegalovirus Therapy 体内母胎来特莫韦暴露及生理药代动力学建模：先天性巨细胞病毒治疗的理论基础 Valentine Faure Bardon and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 848–857, https://doi.org/10.1093/infdis/jiaf619 10 Feasibility and Safety of Aerosolized Influenza Virus Challenge in Humans Using Two Modern Delivery Systems 使用两种现代递送系统进行雾化流感病毒人体激发的可行性与安全性 Nadine Rouphael and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 858–867, https://doi.org/10.1093/infdis/jiaf603 11 Rhinovirus-Associated Lower Respiratory Tract Infection in Hospitalized Adult Patients: A Retrospective Cohort Study 住院成人患者中与鼻病毒相关的下呼吸道感染：一项回顾性队列研究 Rongling Zhang and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 868–876, https://doi.org/10.1093/infdis/jiaf651 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 12 Decoding Hypervirulence in Carbapenem-Resistant Klebsiella pneumoniae: Genomic and Phenotypic Profiling Reveals Capsular Polysaccharide as a Key Driver of Pathogenicity 解码碳青霉烯耐药肺炎克雷伯菌的高毒力：基因组与表型分析揭示荚膜多糖是致病性的关键驱动因素 Li Xu and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 877–887, https://doi.org/10.1093/infdis/jiag075 13 Inflammatory Cytokine Profile in Pregnant Women Colonized With Group B Streptococcus Reveals IL-17a as a Potential Biomarker to Identify at-risk Newborns B族链球菌定植孕妇的炎症细胞因子谱显示IL-17a可作为识别高危新生儿的潜在生物标志物 Narjis Amar and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 888–898, https://doi.org/10.1093/infdis/jiag092 14 Epitope-Based Multimeric Subunit Vaccine (ATOMSSUISpenta) Confers Broad Protection Against Streptococcus suis Infection 表位基多聚体亚单位疫苗（ATOMSSUISpenta）对猪链球菌感染提供广泛保护 Sun-Young Kim and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 899–911, https://doi.org/10.1093/infdis/jiag131 Parasites（寄生虫） 15 Pfs230 Domains 7–10 Encoded by DNA Vaccines Induce Potent Complement-Independent Transmission-Blocking Antibody Against Plasmodium falciparum DNA疫苗编码的Pfs230结构域7–10可诱导强效非补体依赖性抗恶性疟原虫传播阻断抗体 Yi Cao and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 912–923, https://doi.org/10.1093/infdis/jiaf555 16 Uneven Plasmodium falciparum Transmission and Cryptic ovale Transmission From the Asymptomatic Reservoir in Bagamoyo, Tanzania 坦桑尼亚巴加莫约无症状感染库中恶性疟原虫传播不均与隐匿性卵形疟原虫传播 Jessica T Lin and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 924–933, https://doi.org/10.1093/infdis/jiaf634 17 Mzb1 Promotes Progression of Schistosomiasis by Inducing Endoplasmic Reticulum Stress Mzb1通过诱导内质网应激促进血吸虫病进展 Lanyue Pan and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 934–945, https://doi.org/10.1093/infdis/jiaf639 Antimicrobial Resistance (AMR)（抗生素耐药） 18 Longitudinal Trends in Pediatric Non-Salmonella Gram-Negative Enterobacterales Infections at a Tertiary Care Center in West Africa, 2005–2023 西非一家三级医疗中心2005–2023年儿童非沙门氏菌革兰阴性肠杆菌科感染的纵向趋势 Sumanth Cherukumilli and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 946–956, https://doi.org/10.1093/infdis/jiag027 19 The Effect of a 5-Day Course of Azithromycin on Streptococcus Pneumoniae Carriage and Antimicrobial Resistance Among Kenyan Children Discharged From Hospital 阿奇霉素5天疗程对出院肯尼亚儿童肺炎链球菌携带率及抗菌药物耐药性的影响 Tanya E Libby and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 957–965, https://doi.org/10.1093/infdis/jiag028 20 Comparative Analysis of High-Dose Dual Therapies in First-Line Helicobacter pylori Eradication: An Inverse Probability of Treatment-Weighted Multicenter Study 高剂量双联方案一线幽门螺杆菌根除治疗的比较分析：一项逆概率加权多中心研究 Qingzhou Kong and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages 966–974, https://doi.org/10.1093/infdis/jiag059 Editorial（社论） 21 Implementation Does Not Occur in a Vacuum: Sustaining a Comprehensive and Global Vision for HIV Research 实施并非在真空中发生：维持全面且全球化的HIV研究愿景 Sara Gianella and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1085–e1087, https://doi.org/10.1093/infdis/jiag063 22 Uncovering the Hidden Impacts of Modern Medicine's Expanding Pharmacopeia on Clostridioides difficile Infection Risk  揭示现代医学不断扩展的药物谱对艰难梭菌感染风险的隐性影响 Alison Laufer Halpin and L Clifford McDonald The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1088–e1091, https://doi.org/10.1093/infdis/jiag011 Perspectives（观点） 23 Future Directions for NIH HIV Research: A Look Ahead to 2026 美国国立卫生研究院HIV研究的未来方向：展望2026年 Geri R Donenberg and Robert W Eisinger The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1092–e1093, https://doi.org/10.1093/infdis/jiag062 ID Translational Science Update（传染病转化医学更新） 24 Immune Responses to Phage Therapy in Humans: A Review  人体对噬菌体疗法的免疫应答：综述 Kiran Bosco and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1094–e1103, https://doi.org/10.1093/infdis/jiag096 Major Articles and Brief Reports（主要论著与简报） Bacterial Disease Pathogenesis（细菌性疾病发病机制） 25 Antibiotic and Nonantibiotic Drugs Associated With Clostridioides difficile Infection Risk: a Pharmacopoeia-Wide Case-Cohort Study  与艰难梭菌感染风险相关的抗菌及非抗菌药物：一项全药物谱病例-队列研究 Kevin A Brown and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1104–e1114, https://doi.org/10.1093/infdis/jiag001 26 Age-Specific Concentrations and Seroprevalence of Antibodies Against Salmonella Enteritidis (O:9) and Salmonella Typhimurium (O:4,5) Across 3 Sites in Kenya  肯尼亚3个地区针对鼠伤寒沙门氏菌（O:9）和伤寒沙门氏菌（O:4,5）抗体的年龄特异性浓度与血清流行率 Esther M Muthumbi and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1115–e1123, https://doi.org/10.1093/infdis/jiag114 27 Influence of Chlamydia trachomatis Sequence Variation on pgp3 Antigenicity 沙眼衣原体序列变异对pgp3抗原性的影响 Filomeno Coelho da Silva and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1124–e1129, https://doi.org/10.1093/infdis/jiag067 28 Increased Diversity and Introduction of Multidrug-Resistant Strains of Neisseria gonorrhoeae Following Cessation of COVID-19 Pandemic–Related Travel Restrictions: An Observational Genomic Epidemiologic Study  新冠疫情相关旅行限制解除后淋病奈瑟菌多样性增加及多重耐药菌株的引入：一项观察性基因组流行病学研究 Rosa C Coldbeck-Shackley and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1130–e1140, https://doi.org/10.1093/infdis/jiag097 29 Disease-Attenuated Pneumococcal Biosynthesis Gene Mutants Invade the Mucosal Epithelium and Induce Innate Immunity  致病性减弱的肺炎链球菌生物合成基因突变体可侵入黏膜上皮并诱导先天免疫 Caroline M Weight and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1141–e1153, https://doi.org/10.1093/infdis/jiag124 HIV/AIDs（人类免疫缺陷病毒/艾滋病） 30 Functional and Transcriptional Senescence Profiles of CD8+ T Cells Associate With the Presence of Carotid Plaques in People Living With HIV  HIV感染者中CD8+ T细胞的功能及转录衰老特征与颈动脉斑块有关 Marc J T Blaauw and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1154–e1164, https://doi.org/10.1093/infdis/jiag018 31 Estimating HIV-1 Viremic Time From Reservoir Sequence Diversity With Uncertainty Quantification 利用库序列多样性估算HIV-1病毒血症时间及不确定性量化 Edward N Kankaka and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1165–e1172, https://doi.org/10.1093/infdis/jiag020 32 Longitudinal Changes in Cognition and Brain Imaging in Persons With Human Immunodeficiency Virus  人类免疫缺陷病毒感染者认知功能与脑影像学的纵向变化 James Kennedy and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1173–e1180, https://doi.org/10.1093/infdis/jiag029 Antimicrobial Resistance (AMR)（抗生素耐药） 33 Epidemiological and Molecular Surveillance of Multiresistant Citrobacter freundii Complex in a Tertiary Care Hospital: A Retrospective Cohort Study  三级医疗机构中多重耐药弗氏柠檬酸杆菌复合群的流行病学与分子监测：一项回顾性队列研究 Pérince Fonton and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1181–e1192, https://doi.org/10.1093/infdis/jiag066 34 The Influence of National Antibiotic Consumption on Neisseria Gonorrhoeae Antibiotic Resistance in Norway, 2003–2024  2003–2024年挪威全国抗生素消耗对淋病奈瑟菌耐药性的影响 Patricia Campbell The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1193–e1202, https://doi.org/10.1093/infdis/jiag076 35 Restoration of Mucosa-Associated Invariant T-Cell Function in Healthcare-Associated Bacterial Infections Supports Recovery of Carbapenem Efficacy Against Resistant Bacteria Ex Vivo  医疗相关细菌感染中黏膜相关恒定T细胞功能的恢复支持碳青霉烯类药物对耐药菌疗效的体外恢复 Yiting Xue and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1203–e1214, https://doi.org/10.1093/infdis/jiag151 Parasites（寄生虫） 36 Febrile Temperature Augments Ring-stage Plasmodium falciparum Adhesion to Brain Endothelial Cells  发热温度增强环期恶性疟原虫对脑内皮细胞的黏附 Fatou Joof and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1215–e1225, https://doi.org/10.1093/infdis/jiaf474 37 Safety, Tolerability, and Pharmacokinetics of 6-Diazo-5-Oxo-L-Norleucine in Malawian Adults With and Without Malaria: A Phase 1 Dose-Escalation Clinical Trial 6-重氮-5-氧代-L-正亮氨酸在马拉维有无疟疾成年人群中的安全性、耐受性与药代动力学：一项1期剂量递增临床试验 Brittany A Riggle and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1226–e1237, https://doi.org/10.1093/infdis/jiag121 38 Tracking Plasmodium knowlesi Through Fecal DNA for Monitoring Zoonotic Transmission in Wild Macaques Across Southeast and South Asia  通过粪便DNA追踪诺氏疟原虫以监测东南亚和南亚野生猕猴中的人畜共患传播 Dhammika Leshan Wannigama and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1238–e1243, https://doi.org/10.1093/infdis/jiag128 Viruses（病毒） 39 Effectiveness of Measles-Mumps-Rubella Vaccination Among Persons Residing in a Congregate Migrant Shelter During a Measles Outbreak: An Observational Cohort Study  麻疹爆发期间聚集性移民收容所居住者麻疹-腮腺炎-风疹疫苗的有效性：一项观察性队列研究 Chelsea S Lutz and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1244–e1252, https://doi.org/10.1093/infdis/jiaf650 40 Quantifying the Impact of Switching From Rotarix to Rotavac Rotavirus Vaccine in Ghana  量化加纳从Rotarix转换为Rotavac轮状病毒疫苗的影响 Ernest O Asare and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1253–e1260, https://doi.org/10.1093/infdis/jiag003 41 Persistent T Cell Immunity Following Nipah Virus Infection: Evidence From Malaysian Survivors  尼帕病毒感染后T细胞免疫的持续存在：来自马来西亚幸存者的证据 Puteri Ainaa S Ibrahim and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1261–e1266, https://doi.org/10.1093/infdis/jiag017 42 Characterization of Mouse-Adapted Marburg and Ravn Viruses in Inbred BALB/c and Outbred CD-1 Mice  BALB/c近交系与CD-1远交系小鼠中适应小鼠的马尔堡病毒与拉文病毒的特征研究 Katherine A Davies and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1267–e1272, https://doi.org/10.1093/infdis/jiag019 43 Cross-reactive H5N1 Neuraminidase Antibodies by Age and Influenza A Imprinting Cohorts of the Past Century: Population-Based Serosurvey, British Columbia, Canada  过去一个世纪不同年龄与甲型流感印记队列中H5N1神经氨酸酶交叉反应抗体：加拿大不列颠哥伦比亚省人群血清学调查 Danuta M Skowronski and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1273–e1284, https://doi.org/10.1093/infdis/jiag030 44 Inflammasome Activation and Oxidative Stress in SARS-CoV-2 Infection and Symptomatic Rebound SARS-CoV-2感染及症状反弹中的炎症小体激活与氧化应激 Silvia Lucena Lage and others The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1285–e1297, https://doi.org/10.1093/infdis/jiag037 Letters to the Editor（致编辑的信） 45 Reply to Gianella: Redefining Science Together 致Gianella的回复：共同重新定义科学 Rachel A Bender Ignacio The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1298–e1299, https://doi.org/10.1093/infdis/jiaf644 46 Response to the Day I Was Told I Wasn’t Doing Science—And Why I’m Grateful for It 对《被告知我没有在做科学的那一天——以及我为何对此心怀感激》的回应 Darcy Wooten The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Page e1300, https://doi.org/10.1093/infdis/jiag084 47 Reply to Gianella: Women in Academic Medicine Will Lead a Sea Change 致Gianella的回复：女性学者将引领学术医学的海变 Maile A Y Karris The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Page e1301, https://doi.org/10.1093/infdis/jiag109 48 Between Two Standards: Reflections on the Double Bind From a Female Chinese Infectious Disease Physician 两种标准之间：一位中国女性传染病医生对双重束缚的反思 Nan Xu The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1302–e1303, https://doi.org/10.1093/infdis/jiag101 49 When “Logistics”Becomes Science: A Research Coordinator's Response on Team-Based Discovery 当"后勤"变成科学：一位研究协调员关于团队协作发现的回应 Cheryl Dullano The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Page e1304, https://doi.org/10.1093/infdis/jiag102 50 Pushing the Stone Uphill Together 共同推石上山 Scott L Letendre The Journal of Infectious Diseases, Volume 233, Issue 5, 15 May 2026, Pages e1305–e1306, https://doi.org/10.1093/infdis/jiag125 The Journal of Infectious Diseases. Volume 233 Issue 6 传染病杂志 233卷 6期 https://academic.oup.com/jid/issue/ Editorial（社论） 1 Increasing Handgrip Strength to Combat Frailty in Human Immunodeficiency Virus: Linking Immune Exhaustion to a Bone Health Indicator 提高握力以对抗人类免疫缺陷病毒患者的衰弱：将免疫耗竭与骨健康指标相联系 Jean-Pierre Routy and Stephane Isnard The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 975–976, https://doi.org/10.1093/infdis/jiag082 2 Immune Checkpoint Inhibition Therapy Beyond the Tumor: Implications for Hepatitis B Virus in Hepatocellular Carcinoma 免疫检查点抑制疗法在肿瘤之外的应用：对肝细胞癌中乙型肝炎病毒的启示 Renato Bobadilla and Arthur Y Kim The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 977–980, https://doi.org/10.1093/infdis/jiag058 Perspective（观点） 3 The Recurring Issue of Syphilis in Europe: Comment on “Ancient Genomes Reveal a Deep History of Treponema pallidum in the Americas” 欧洲梅毒的反复问题——评《古代基因组揭示美洲苍白密螺旋体的深层历史》 M Dehmane and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 981–982, https://doi.org/10.1093/infdis/jiag022 ID Translational Science Update（传染病转化医学最新动态） 4 Evidence-Based Assessment of the Role of Pharyngeal Gonorrhea and Commensal Neisseria Species in the Emergence of Antimicrobial Resistance in Neisseria Gonorrhoeae: Data Gaps and Future Research  咽部淋病与共生奈瑟菌属在淋病奈瑟菌耐药性出现中作用的循证评估：数据缺口与未来研究 Amber D Kimble and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 983–994, https://doi.org/10.1093/infdis/jiag197 Major Articles and Brief Reports（论著与简报） HIV/AIDs（人类免疫缺陷病毒/艾滋病） 5 Frailty in People with HIV Is Linked to Inflammation, Bone Health, and T-Cell Exhaustion  HIV感染者的衰弱与炎症、骨健康及T细胞耗竭相关 Michael L Freeman and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 995–1004, https://doi.org/10.1093/infdis/jiag046 6 A New Type of Nonsuppressible Viremia Produced by HIV-Infected Macrophage HIV感染巨噬细胞产生的一种新型不可抑制性病毒血症 Matthew J Moeser and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1005–1014, https://doi.org/10.1093/infdis/jiag171 Viral Disease Pathogenesis（病毒性疾病发病机制） 7 Immune Checkpoint Inhibitor-Induced Rapid Decline in Hepatitis B Virus Markers Improves the Prognosis of Hepatitis B Virus–Related Hepatocellular Carcinoma Patients 免疫检查点抑制剂诱导的乙型肝炎病毒标志物快速下降改善乙肝相关肝细胞癌患者的预后 Yujie Ran and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1015–1026, https://doi.org/10.1093/infdis/jiag036 8 Nasal Biomarkers of Acute Illness Severity and Predictors of Recurrent Wheeze in Infants Infected With Respiratory Syncytial Virus 呼吸道合胞病毒感染婴儿的急性疾病严重程度的鼻部生物标志物及反复喘息的预测因素 Mary T Caserta and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1027–1035, https://doi.org/10.1093/infdis/jiag049 9 Epidemiological, Clinical, and Virological Characterizations of Yezo Virus Infections, an Emerging Tick-borne Orthonairovirus Disease in Japan 日本新兴蜱传正内罗病毒病——耶佐病毒感染的流行病学、临床及病毒学特征 Hiroki Yamaguchi and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1036–1045, https://doi.org/10.1093/infdis/jiag073 10 Single-Cell Sequencing Reveals Varying Cell-Mediated Immunity Profiles in Individuals With Distinct Antibody Responses Following Ad5-nCoV Booster 单细胞测序揭示Ad5-nCoV加强针接种后不同抗体应答者的细胞免疫谱差异 Conghui Liao and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1046–1057, https://doi.org/10.1093/infdis/jiag078 11 Middle East Respiratory Syndrome Coronavirus–Specific T-Cell Responses in Dromedary Camel Abattoir Workers in Nigeria Suggests Frequent Zoonotic Spillover 尼日利亚单峰驼屠宰场工人中中东呼吸综合征冠状病毒特异性T细胞反应提示频繁的人畜共患溢出 Chris K P Mok and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1058–1062, https://doi.org/10.1093/infdis/jiag095 12 Incidence and Severity of Postacute Sequelae of SARS-CoV-2 Infection in the Omicron Era: A Prospective Cohort Study 奥密克戎时代SARS-CoV-2感染后急性后遗症的发生率与严重程度：一项前瞻性队列研究 Dan-Yu Lin and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1063–1068, https://doi.org/10.1093/infdis/jiag026 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 13 Real-World Effectiveness of Sequential Pneumococcal Vaccination in Older Adults: A Cohort Study 老年人序贯肺炎球菌疫苗接种的现实有效性：一项队列研究 Yong Yi Tan and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1069–1080, https://doi.org/10.1093/infdis/jiag147 14 Safety and Immunogenicity of a Trivalent Salmonella Conjugate Vaccine to S. Typhi, S. Typhimurium, and S. Enteritidis 针对伤寒沙门氏菌、鼠伤寒沙门氏菌和肠炎沙门氏菌的三价沙门氏菌结合疫苗的安全性与免疫原性 Wilbur H Chen and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1081–1090, https://doi.org/10.1093/infdis/jiag156 15 The Natural History of Mycoplasma genitalium in the Pharynx and Rectum in a Cohort of Men Who Have Sex With Men: Prevalence, Incidence, Duration, and Symptoms 生殖支原体在男男性行为者咽部和直肠中的自然史：患病率、发病率、持续时间及症状 Lindley A Barbee and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1091–1099, https://doi.org/10.1093/infdis/jiag173 16 A Genomic Analysis of Community-Associated C. difficile Infection Demonstrates Integration With National and International Strain Clusters and Limited Direct Transmission 社区相关性艰难梭菌感染的基因组分析显示其与国内外菌株簇的整合及有限的直接传播 Nicole D Pecora and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1100–1109, https://doi.org/10.1093/infdis/jiag176 Antimicrobial Resistance (AMR)（抗生素耐药） 17 Recurrent Plasmodium falciparum Parasitemia and Drug Resistance Mutations During Intermittent Preventive Treatment of Malaria in Pregnancy in Uganda 乌干达妊娠期疟疾间歇性预防治疗期间恶性疟原虫复现及耐药突变 Jimmy Kizza and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1110–1119, https://doi.org/10.1093/infdis/jiag074 18 Stepwise Evolution of Triple Antimicrobial Resistance in Neisseria meningitidis 脑膜炎奈瑟菌三重耐药性的逐步演化 José Eduardo O Marín and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1120–1129, https://doi.org/10.1093/infdis/jiag113 19 Asymptomatic Screening for Neisseria gonorrhoeae Among Gay and Bisexual Men Attending Public Sexual Health Services in Australia and Associations With Patterns of Ceftriaxone Consumption: A Retrospective Observational Study 澳大利亚男男性行为者在公共性健康服务机构中淋病奈瑟菌无症状筛查及其与头孢曲松消费模式的关联：一项回顾性观察研究 Arthur Wong and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages 1130–1140, https://doi.org/10.1093/infdis/jiag192 Editorial（社论） 20 Cytomegalovirus and Aging—How Can the Field Move Forward?  巨细胞病毒与衰老——该领域如何向前推进？ Michael Boeckh and Lawrence Corey The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1307–e1309, https://doi.org/10.1093/infdis/jiag099 21 New Insights From Perinatal HIV: A Way Forward for HIV Cure Research 围产期HIV的新见解——HIV治愈研究的前进方向 Rajesh T Gandhi and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1310–e1312, https://doi.org/10.1093/infdis/jiag057 ID Translational Science Update（传染病转化医学最新动态） 22 What's Hot in HIV in 2025—A Basic and Translational Science Review From IDWeek 2025  2025年HIV研究热点——IDWeek 2025基础与转化医学综述 Ana Rafaela Teixeira and Marina Caskey The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1313–e1319, https://doi.org/10.1093/infdis/jiag135 Major Articles and Brief Reports（论著与简报） Viruses（病毒） 23 A Pathogen Penalty? Associations Between Persistent Infections and Biological Aging in the US  病原体惩罚？美国持续感染与生物学衰老之间的关联 Jennifer Momkus and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1320–e1329, https://doi.org/10.1093/infdis/jiaf606 24 Transient Interferon-Driven Natural Killer Cell Activation in Acute Hepatitis C  急性丙型肝炎中一过性干扰素驱动的自然杀伤细胞激活 Benedikt Strunz and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1330–e1340, https://doi.org/10.1093/infdis/jiaf654 25 Risk-Based Prophylactic Human Papillomavirus Vaccination of Heterosexual US Men Aged 27 to 45 Years for Prevention of Oropharyngeal Cancer 基于风险用以预防口咽癌的美国男性27至45岁异性恋人群预防性人乳头瘤病毒疫苗接种 Anil K Chaturvedi and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1341–e1344, https://doi.org/10.1093/infdis/jiag038 26 Machine Learning–Enabled Quantification of Hepatocellular Necrosis in the Liver After Lethal Marburg and Ebola Virus Exposures 机器学习辅助定量分析致死性马尔堡病毒和埃博拉病毒暴露后肝脏肝细胞坏死程度 Yanling Liu and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1345–e1354, https://doi.org/10.1093/infdis/jiag040 27 Influenza Vaccination Effectiveness Against Influenza-Associated Hospitalization in Children and the Effects of Repeated Vaccination  流感疫苗对儿童流感相关住院的有效性及重复接种的影响 Xuan Yu and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1355–e1363, https://doi.org/10.1093/infdis/jiag047 28 Repeat Influenza Vaccination Effects in 2021/22 and 2022/23 in a Community-Based Cohort in Hong Kong  2021/22及2022/23季香港社区队列中重复接种流感疫苗的效果 Jennifer C Zhong and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1364–e1373, https://doi.org/10.1093/infdis/jiag051 29 Anti-spike IgG Avidity Enhances Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2: A Prospective Study of Primary Infections and Immunizations  抗刺突蛋白IgG亲合力增强对严重急性呼吸综合征冠状病毒2的中和作用：初次感染与免疫接种的前瞻性研究 Visa Nurmi and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1374–e1385, https://doi.org/10.1093/infdis/jiag068 30 Genomic Evolution of Influenza A Virus During the 2024–2025 Season, the Johns Hopkins Health System: Antigenic Drift Reduces Serum Neutralization  2024—2025季约翰斯·霍普金斯卫生系统中甲型流感病毒的基因组进化：抗原漂移降低血清中和能力 David Villafuerte and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1386–e1395, https://doi.org/10.1093/infdis/jiag069 HIV/AIDs（人类免疫缺陷病毒/艾滋病） 31 Dynamics of Intact and Defective Human Immunodeficiency Virus Type 1 (HIV-1) Proviruses During Decades of Suppressive Antiretroviral Treatment in Young Adults With Perinatal HIV  围产期感染HIV青年人在数十年抑制性抗逆转录病毒治疗期间完整与缺陷型人类免疫缺陷病毒1型（HIV-1）前病毒的动态变化 Priya Khetan and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1396–e1406, https://doi.org/10.1093/infdis/jiag045 32 Unsuppressed Viremia and Lower CD4 Count Associated With Faster Telomere Attrition in African Children With Perinatal Human Immunodeficiency Virus on Long-term Antiretroviral Therapy  未抑制的病毒血症及较低CD4计数与长期接受抗逆转录病毒治疗的非洲围产期感染HIV的儿童端粒加速缩短相关 Julian P G Shellard and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1407–e1417, https://doi.org/10.1093/infdis/jiag060 33 Limited Sex-Based Differences in Viral Outcomes of ART-Treated SIV/SHIV Infection  ART治疗的SIV/SHIV感染中病毒学结局的性别差异有限 Kedan Endrias and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1418–e1422, https://doi.org/10.1093/infdis/jiag064 34 Mitochondrial Haplogroups and Left Ventricular Diastolic Dysfunction in People Living With and Without HIV  线粒体单倍群与HIV感染者及非感染者的左心室舒张功能障碍 Craig Cronin and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1423–e1432, https://doi.org/10.1093/infdis/jiag090 Bacterial Disease Pathogenesis（细菌性疾病发病机制） 35 Cefazolin Inoculum Effect and Cefazolin Microbiological Treatment Failure in Serious Methicillin-Susceptible Staphylococcus aureus Infections: A Multicenter Retrospective Cohort Study  甲氧西林敏感金黄色葡萄球菌严重感染中头孢唑林接种效应与微生物学治疗失败：一项多中心回顾性队列研究 Mitchell A Jeffs and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1433–e1442, https://doi.org/10.1093/infdis/jiag199 36 Investigation of Correlates of Protection Against Gonococcal Infection by Comparative Immunoprofiling of Responses in Experimental and Clinical Studies  通过实验和临床研究中免疫反应的比较分析，探究淋球菌感染保护的相关因素 Samantha A McKeand and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1443–e1453, https://doi.org/10.1093/infdis/jiag216 Parasites（寄生虫） 37 Schistosoma mansoni Infections Are Associated With Fecal Calprotectin Markers of Gut Inflammation After Accounting for HIV, Hepatitis B, and Malaria  在控制HIV、乙型肝炎和疟疾因素后，曼氏血吸虫感染与肠道炎症粪便钙卫蛋白标志物相关 Lauren Wilburn and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1454–e1464, https://doi.org/10.1093/infdis/jiag094 38 Expelling of Plasmodium falciparum Sporozoites by Anopheles stephensi Mosquitoes During Repeated Feeding  按蚊在反复吸血过程中驱逐恶性疟原虫子孢子 Chiara Andolina and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1465–e1469, https://doi.org/10.1093/infdis/jiag130 39 Predicting Risk of Plasmodium Vivax Microscopy-Detected Episodes Using Serological Markers in Patients With Plasmodium falciparum Malaria: A Multicountry Diagnostic Performance Evaluation  利用血清学标志物预测恶性疟原虫疟疾患者中间日疟原虫镜检检出发作的风险：一项多国诊断效能评估 Maulina Hafidzah and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1470–e1479, https://doi.org/10.1093/infdis/jiag164 40 Hidden Infections, Emerging Resistance: Underdiagnosed Plasmodium vivax and Multidrug Resistance-1 (pvmdr1) Gene Amplification in the Guiana Shield  隐匿感染，耐药新兴：圭亚那盾区漏诊的间日疟原虫及多药耐药基因1（pvmdr1）基因扩增 Maria Carolina Silva de Barros Puça and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1480–e1489, https://doi.org/10.1093/infdis/jiag196 Fungi（真菌） 41 Treatment Monitoring and Outcome Prediction in Invasive Aspergillosis Using Immunologic Markers  利用免疫学标志物监测侵袭性曲霉病的治疗效果及预后预测 Ana Pereira and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1490–e1499, https://doi.org/10.1093/infdis/jiag140 42 MHC-I Upregulation and Increased Glucose Dependence Define Innate Antifungal Immune Responses to Cryptococcus neoformans  MHC-I上调及葡萄糖依赖性增加是针对新型隐球菌的先天抗真菌免疫应答的特征 Ayesha S Nair and Karen L Wozniak The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1500–e1510, https://doi.org/10.1093/infdis/jiag144 Letters to the Editor（致编辑的信） 43 Infectious Disease Risk Management in Body Donation Programs 遗体捐献项目中的传染病风险管理 Brandi Schmitt and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1511–e1512, https://doi.org/10.1093/infdis/jiaf579 44 In Response to Schmitt et al: Data Do Not Support Exclusionary Policies 回应Schmitt等人：数据不支持排斥性政策 Sara Gianella and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1513–e1515, https://doi.org/10.1093/infdis/jiaf580 45 CXCR6 in the Blood Is Not the Liver: Clarifying NK-Cell “Homing” and Postcure ADCC Imprints in Acute Hepatitis C 血液中的CXCR6不等于肝脏：澄清急性丙型肝炎中NK细胞"归巢"及治愈后ADCC印迹 Anxin Wen The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1516–e1517, https://doi.org/10.1093/infdis/jiag044 46 Holding One Another in a Time of Loss and Uncertainty 在失去与不确定的时代中彼此守望 Sara Gianella The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1518–e1519, https://doi.org/10.1093/infdis/jiag110 47 Comment on “Comparative Analysis of High-Dose Dual Therapies in First-Line Helicobacter pylori Eradication: An Inverse Probability of Treatment-Weighted Multicenter Study” 评《高剂量双联方案一线根除幽门螺杆菌的比较分析：一项基于逆概率治疗加权的多中心研究》 Guofu Mao and others The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1520–e1521, https://doi.org/10.1093/infdis/jiag139 Corrections（勘误） 48 Correction to: Epidemiology and Risk Factors of Norovirus Infections Among Diarrhea Patients Admitted to Tertiary Care Hospitals in Bangladesh  勘误：孟加拉国三级医院腹泻住院患者中诺如病毒感染的流行病学及危险因素 The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Page e1522, https://doi.org/10.1093/infdis/jiag234 49 Correction to: Rickettsia rickettsii subsp californica subsp nov, the Etiologic Agent of Pacific Coast Tick Fever  勘误：立克次体加州亚种新亚种——太平洋海岸蜱传热的病原体 The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Pages e1523–e1524, https://doi.org/10.1093/infdis/jiag016 50 Correction to: Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants  勘误：杂合B细胞和T细胞免疫与严重急性呼吸综合征冠状病毒2疫苗接种后突破性感染的保护相关——艾文纵向父母与儿童研究（ALSPAC）参与者分析 The Journal of Infectious Diseases, Volume 233, Issue 6, 15 June 2026, Page e1525, https://doi.org/10.1093/infdis/jiag161