Signal Transduction and Targeted Therapy最新文献

{"title":"Real-world renoprotective effects of polyethylene glycol-loxenatide in type 2 diabetes: a multicenter, ambispective cohort study.","authors":"Junjun Ye, Jilin Li, Yongsong Chen, Fengwu Chen, Dan Zhu, Chuangyan Zhang, Qianyi Chen, Yu Tian, Shuhui Yang, Wencan Xu, Bin Xie, Zhe-Sheng Chen, Kaijian Hou","doi":"10.1038/s41392-026-02945-5","DOIUrl":"https://doi.org/10.1038/s41392-026-02945-5","url":null,"abstract":"<p><p>Patients with type 2 diabetes mellitus and chronic kidney disease face persistent risks despite standard care. Polyethylene glycol-loxenatide lacks real-world renoprotective evidence in high-risk Chinese populations relative to non-incretin-based standard care. This multicenter, ambispective cohort study enrolled 3305 patients with type 2 diabetes mellitus, renal impairment, and elevated cardiovascular risk at six Chinese tertiary institutions (median follow-up 36.4 months; trial registration: ChiCTR2300073001). Data were extracted via an artificial intelligence-enhanced pipeline. Co-primary analyzes comprised multivariable-adjusted Cox regression and 1:1 propensity score matching (332 per group); pre-specified landmark analyzes at 6 and 12 months addressed immortal time bias. Polyethylene glycol-loxenatide was associated with a reduced risk of the primary kidney composite outcome in the original cohort (hazard ratio [HR], 0.49; 95% CI, 0.25-0.95; P = 0.035), which was corroborated in the propensity score matched cohort (HR, 0.44; 95% CI, 0.20-0.97; P = 0.043) and progressive across 6-month (HR, 0.40; 95% CI, 0.19-0.84) and 12-month (HR, 0.33; 95% CI, 0.14-0.75) landmarks. While a reduction in 3-point major adverse cardiovascular events was observed in the unmatched cohort (HR, 0.60; 95% CI, 0.43-0.85; P = 0.004), this association was not sustained in the matched analysis (HR, 0.92; 95% CI, 0.57-1.48; P = 0.735). In conclusion, long-term therapy was associated with an attenuated risk of major renal events. Given the null findings in the matched cohort, the cardiovascular observations are exploratory and require randomized confirmation.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration.","authors":"Eileen Victoria Theune, William C Theune, Elham Ahmadi, Conner C Chiari, Neha Singh, Rory Geyer, Jason Tonne, Muriel Metko, Olamide T Olaoba, Isabella China Wang, Dylan Dai, Jianbin Ruan, Robert Clark, Guangfu Li, Penghua Wang, Evan R Jellison, Anthony T Vella, Richard Vile, Kepeng Wang","doi":"10.1038/s41392-026-02888-x","DOIUrl":"https://doi.org/10.1038/s41392-026-02888-x","url":null,"abstract":"<p><p>The lack of tumor-specific targeting by oncolytic viruses (OVs) restricts their therapeutic potential. Here, we report a \"cap-linker\" strategy to modify the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-G^IN). The modified VSV (Pro-VSV^IN) loses its ability to infect cells until present in the tumor microenvironment, where the linker is cleaved by tumor-enriched matrix metalloproteinases (MMPs). When Pro-VSV^IN is armed with a single-chain IL-12 (Pro-VSV^IN-IL-12) and systemically injected into MC38 tumor-bearing mice, Pro-VSV^IN-IL-12 eradicates established tumors while avoiding systemic toxicity, and elicits long-term anti-tumor immune memory. Systemic administration of Pro-VSV^IN-IL-12 also markedly inhibits the growth of metastatic cancers in the lung. The efficacy of Pro-VSV^IN-IL-12 was further improved when combined with PD-1 checkpoint blockade. Compared to WT VSV^IN that carries IL-12, intravenously injected Pro-VSV^IN-IL-12 leads to strong Th1 immunity, near abolishment of regulatory T cells, and potent CD8⁺ T cell activation and clonal expansion in tumors. This preclinical work demonstrates a new tumor-specific targeting strategy of VSV for enhanced immunotherapy safety with superior efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitophagy coordinates organelle crosstalk in health and diseases.","authors":"Mengyao Wu, Pengyi He, Yajun Lian, Tuo Zhang, Yiqi Wu, Lu Wang, Daolin Tang, Yongming Yao, Renqi Yao","doi":"10.1038/s41392-026-02812-3","DOIUrl":"https://doi.org/10.1038/s41392-026-02812-3","url":null,"abstract":"<p><p>Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine context shapes antigen-presenting and matrix-producing states of cancer-associated fibroblasts.","authors":"Feifei Song, Qi Chen, Dengfeng Huang, Youhua Zhang, Dongyan Han, Wei Rao, Man Li, Yaohui Gao, Renfeng Zhang, Huiyuan Zhu, Shufei Wang, Xiao Jiang, Shengli Lin, Dexi Bi, Haixian Zhang, Qing Wei, Huanlong Qin","doi":"10.1038/s41392-026-02965-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02965-1","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) exhibit remarkable functional heterogeneity, with conserved subtypes observed across diverse malignancies. However, their shared roles in shaping the tumor microenvironment (TME) and their dynamic plasticity remain incompletely understood. In this study, through integrated single-cell and spatial transcriptomic profiling across four cancer types, we identified two distinct immunomodulatory CAF states, termed antigen-presenting CAFs (apCAFs) and matrix-producing CAFs (mCAFs). Across multiple solid tumors, apCAFs were associated with enhanced anti-tumor immune features and favorable prognosis, whereas mCAFs were associated with immunosuppressive characteristics and poorer clinical outcomes. Spatial analyses revealed distinct localization patterns of apCAFs and mCAFs within the TME. Functionally, patient-derived apCAFs promoted T-cell migration, proliferation, and activation, whereas mCAFs suppressed these responses in vitro. Pan-cancer analyses further revealed a strong inverse correlation between apCAF and mCAF abundance across tumor tissues. Mechanistically, IFN-γ and TGF-β-associated signaling contexts were linked to distinct CAF transcriptional programs, with IFN-γ promoting apCAF-associated features and TGF-β favoring mCAF-associated features, suggesting a potential role of cytokine context in shaping CAF state heterogeneity. Clinically, apCAFs correlated with favorable immunotherapy response, whereas mCAFs predicted poor therapeutic outcomes. Collectively, these findings identify conserved immunomodulatory CAF subtypes across cancers, reveal distinct cytokine-associated CAF programs, and support stromal reprogramming as a promising strategy to enhance immunotherapy efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Entinostat plus exemestane for hormone receptor-positive advanced breast cancer: long-term overall survival results from the EOC103A3101 randomized controlled trial.","authors":"Jiani Wang, Qingyuan Zhang, Xichun Hu, Tao Sun, Wei Li, Quchang Ouyang, Jingfen Wang, Zhongsheng Tong, Min Yan, Huiping Li, Xiaohua Zeng, Changping Shan, Xian Wang, Jian Zhang, Yue Zhang, Liang Zhang, Hongyan Shang, Binghe Xu","doi":"10.1038/s41392-026-02899-8","DOIUrl":"https://doi.org/10.1038/s41392-026-02899-8","url":null,"abstract":"<p><p>The addition of entinostat, a histone deacetylase inhibitor, to exemestane has demonstrated improved progression-free survival (PFS) in hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) following endocrine therapy failure in the EOC103A3101 randomized trial (NCT03538171). This study reports long-term overall survival (OS) results. In this study, 354 patients with HR + /HER2- ABC that had recurred or progressed after endocrine therapy were randomized (2:1) to receive entinostat plus exemestane (n = 235) or placebo plus exemestane (n = 119). After a median follow-up of 31.8 months, the median OS was 38.6 months (95% confidence interval [CI]: 29.6-44.0) in the entinostat-exemestane group versus 29.2 months (95% CI: 22.5-41.6) in the placebo-exemestane group (hazard ratio [HR] 0.83, 95% CI: 0.62-1.10, P = 0.184). The entinostat-exemestane group demonstrated more pronounced OS benefits when adjusting subsequent antitumor therapies such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, or the combination of endocrine therapy, CDK4/6 inhibitors, and chemotherapy. The sensitivity analysis based on the per-protocol set showed more significant OS benefits. The median time to post-discontinuation chemotherapy and chemotherapy-free survival in the entinostat-exemestane group were 11.7 and 9.3 months, respectively, compared to 6.8 and 5.6 months in the placebo-exemestane group (both P < 0.05). Grade ≥3 treatment-emergent adverse events occurred in 65.5% of patients in the entinostat-exemestane group, without new safety signals observed. In conclusion, among patients with HR + /HER2- ABC after endocrine therapy failure, entinostat plus exemestane was associated with a numerically longer OS, with an acceptable safety profile.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of ifupinostat in relapsed or refractory diffuse large B-cell lymphoma: a multicenter, single-arm phase 2 study","authors":"Yuankai Shi, Peng Liu, Yufu Li, Wenyu Li, Hui Zhou, Yu Yang, Jie Jin, Yuhuan Gao, Weijie Xu, Meifang Zheng, Haiyan Yang, Hongwei Xue, Zhigang Peng, Ou Bai, Fei Li, Fangfang Lv, Liling Zhang, Ning Huang, Yi Luo, Chunhong Hu, Yajing Xu, Huilai Zhang, Xiuhua Sun, Xin Li, Kaiyang Ding, Linjuan Zeng, Haiyan Zhu, Yajie Cao, Yonglong Yang, Kegang Jiang, Changgeng Qian","doi":"10.1038/s41392-026-02926-8","DOIUrl":"https://doi.org/10.1038/s41392-026-02926-8","url":null,"abstract":"Ifupinostat (BEBT-908) is a novel dual-targeted inhibitor of histone deacetylase (HDACs) and phosphatidylinositol 3-kinase alpha (PI3Kα). We evaluated the efficacy and safety of ifupinostat monotherapy in patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. Eligible participants received intravenous ifupinostat at 22.5 mg/m² on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. From June 2020 to July 2022, 128 patients were enrolled and included in the safety set (SS), and 115 patients were in the efficacy analysis set (EAS). At the data cutoff (July 2023), the median follow-up was 19.58 months (95% confidence interval [CI] 16.82–21.95). The ORR was 36.5% (42/115, 95% CI 27.7-46.0), with a complete response rate of 11.3% (13/115). The median DoR was 6.2 months (95% CI 3.5–14.5), median PFS was 2.7 months (95% CI 1.6–3.7), and median OS was 9.9 months (95% CI 7.8–14.8). Treatment-related adverse events (TRAEs) occurred in 99.2% (127/128) of patients, and ≥grade 3 TRAEs in 86.7% (111/128). The most common ≥grade 3 TRAEs were thrombocytopenia (75.8%, 97/128), neutropenia (33.6%, 43/128), and leukopenia (22.7%, 29/128). No treatment-related deaths occurred. Ifupinostat demonstrated promising efficacy and a manageable safety profile as a new therapeutic alternative for patients with r/r DLBCL. Clinical Trial Registry Number: ChiCTR1900028179.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"21 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic mutations in non-small cell lung cancer: from molecular mechanisms to clinical practice.","authors":"Chaozhuo Li, Xiaoyan Yin, Shujie Zhou, Junxu Wen, Jinming Yu, Xiangjiao Meng","doi":"10.1038/s41392-026-02689-2","DOIUrl":"10.1038/s41392-026-02689-2","url":null,"abstract":"<p><p>Targeted therapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring oncogenic alterations, and next-generation tyrosine kinase inhibitors (TKIs) significantly increase blood-brain barrier (BBB) penetration, leading to improved disease control and survival benefits. However, several issues remain to be addressed, including the selection of more appropriate and individualized agents, the emergence of TKI resistance, and the challenging management of central nervous system (CNS) progression. In this review, we comprehensively summarize the efficacy and safety of TKIs and targeted specific antibodies in advanced or metastatic patients with common or rare mutations, providing guidance in selecting the optimal agent. We further explore the mechanisms underlying drug resistance and regimens aimed at overcoming resistance. In nonmetastatic resectable or unresectable NSCLC, we discuss the therapeutic potential of targeted agents and current issues requiring further research. In addition, we distinguish current and potential therapeutic strategies for patients with baseline brain metastasis (BM) and those without baseline BM who subsequently develop brain progression, leading to more effective and personalized treatment. Finally, we provide perspectives on challenges and future directions in the identification and treatment of oncogenic alterations, particularly in the context of co-mutations and the heterogeneous nature of metastases, and emphasize the clinical importance of artificial intelligence (AI)-assisted genetic testing and biomarker development.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization","authors":"Bei Jin, Shenglan Liu, Hongke Huang, Luo Yang, Dong Wei, Wei Dai, Jingfeng Zhou, Yun Wang, Ping Zhang, Qianyun Ye, Jingxuan Pan","doi":"10.1038/s41392-026-02876-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02876-1","url":null,"abstract":"Liver-organotropic metastasis occurs in cancers such as uveal melanoma (UM) and pancreatic ductal adenocarcinoma (PDAC) and is a leading cause of mortality at the terminal stage. Colonization is a rate-limiting and converging step in the metastatic cascade. The drivers underlying liver colonization have largely remained elusive. In this report, we hypothesized that pioneer transcription factors (TFs) increase chromatin accessibility and superenhancer (SE) remodeling, which subsequently promote colonization-associated cellular features [e.g., proliferation, survival, cancer stem cells (CSCs), motility] by driving the transcription of the respective SE-associated genes. We tested this hypothesis and discovered that the pioneer TF KLF4 promoted chromatin accessibility and SE remodeling by ATAC-seq and ChIP-seq. Chromatin accessibility and SE remodeling significantly increased the transcription of the SE-associated genes MCL1 and RASGRP3, which consequently promoted proliferation, motility, and metastasis. Furthermore, the upregulation of KLF4 expression in UM cells was promoted by RN7SL2-containing exosomes from surrounding endothelial cells. Analysis of clinical datasets revealed that the overexpression of RIG-I, STAT1, KLF4, and RASGRP3 was individually correlated with shorter metastasis-free survival or overall survival in patients with UM and PDAC. In conclusion, the identification of the exoRN7SL2-STAT1-KLF4-SEs-RASGRP3 signaling axis may help elucidate metastatic colonization through interactions between tumor cells and the endothelial niche and may yield novel and viable therapeutic targets.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"482 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation natural killer cell therapy: bench to bedside and beyond.","authors":"Aiqi Zhao, Jing Xu, Wenhai Deng, Minghuan Zhang, Yanping Shao, Yu Liu, Aibin Liang, Xiaobing Wang, Ting Niu, Wenbin Qian","doi":"10.1038/s41392-026-02911-1","DOIUrl":"10.1038/s41392-026-02911-1","url":null,"abstract":"<p><p>Natural killer (NK) cells have emerged as central players in cancer immunotherapy, progressing from basic discovery to clinically validated platforms over five decades. This review synthesizes the evolving understanding of NK cell biology, including subset heterogeneity, epigenetic regulation, and metabolic control, and, as innovative focal points, intratumoral NK heterogeneity, epigenetic modulation, and intracellular immune checkpoints, forming the foundation for rational therapeutic engineering. We examine the clinical trajectory from unmodified adoptive transfer to cytokine-induced memory-like NK cells and, most transformatively, to chimeric antigen receptor (CAR)-NK cells. Landmark trials have established the remarkable efficacy and superior safety of CAR-NK cells in B-cell malignancies, with recent studies extending these benefits to autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis, demonstrating durable immune reset with a favorable safety profile. Despite these advances, solid tumors remain formidable challenges, hindered by antigen heterogeneity, physical barriers, and a metabolically hostile microenvironment. We therefore analyze next-generation engineering strategies that move beyond single modifications toward systems-level reprogramming, encompassing intrinsic enhancements (cytokine signaling, metabolic fitness, checkpoint disruption), extrinsic tumor microenvironment remodeling, and advanced delivery platforms. We further synthesize the practical dimensions of clinical translation by systematically examining key optimization parameters that will guide the path toward precision NK cell therapy. These include rational dosing and scheduling regimens, strategies to reduce lymphodepletion intensity, context-dependent persistence requirements across different disease indications and the emerging biomarker landscape.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of humoral immunity: molecular mechanisms, diseases and therapeutic targets.","authors":"Shaocun Zhang, Yu Wang, Xin Min, Yuzhang Wu, Wanli Liu","doi":"10.1038/s41392-026-02955-3","DOIUrl":"10.1038/s41392-026-02955-3","url":null,"abstract":"<p><p>Humoral immunity, a fundamental branch of adaptive immunity, relies on B lymphocytes and the antibodies they produce to eliminate extracellular pathogens and neutralize toxins. The development, activation, and differentiation of B cells are tightly regulated by epigenetic mechanisms-including DNA methylation, histone modifications, chromatin dynamics, RNA modifications, and noncoding RNAs-that modulate gene expression without altering the DNA sequence, orchestrating key events such as V(D)J recombination, class switch recombination, somatic hypermutation, germinal center reactions, and the generation of memory B cells and plasma cells. In this review, we summarize how these five categories of epigenetic regulators-together with their respective writers, erasers, readers, and effectors-including DNMT3A/3B and TET enzymes, histone-modifying enzymes, SWI/SNF and INO80 remodeling complexes, N6-methyladenosine and 5-methylcytosine machineries, and microRNAs and long noncoding RNAs-collectively govern B-cell fate decisions, from early lineage commitment in the bone marrow, through germinal center dynamics, to terminal differentiation into plasma cells or memory B cells. We further examine how aberrant epigenetic programs in B cells contribute to pathogenesis across four major disease categories: B-cell malignancies, metabolic and cardiovascular diseases, autoimmune disorders, and infectious diseases. We also discuss sex-biased epigenetic mechanisms, particularly escape from X-chromosome inactivation, that may underlie the female predominance of autoimmune diseases. Finally, we discuss the therapeutic implications of targeting epigenetic regulators and assess the potential of epigenetic signatures as biomarkers.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}