Signal Transduction and Targeted Therapy最新文献

{"title":"Glutamine metabolism in health and disease","authors":"Junsheng Zhao,Yajie Lin,Rong Gao,Hainv Gao,Lanjuan Li","doi":"10.1038/s41392-026-02981-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02981-1","url":null,"abstract":"Abstract Glutamine is the most abundant free amino acid in the body. It plays a central role in cellular metabolism, connecting synthetic and catabolic pathways, and maintaining life activities under physiological and pathological conditions. This review systematically explores the dual role of glutamine metabolism in health and disease. Glutamine is not only the main energy and nitrogen source for rapidly proliferating cells, such as immune cells, intestinal epithelial cells, and cancer cells but also participates in several key biological processes, such as nucleotide synthesis, REDOX balance, and immune regulation. Glutamine metabolism is often abnormally activated or disrupted in disease states, such as “glutamine addiction” in cancer and excitotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Disorders of glutamine metabolism are also present in metabolic diseases (such as diabetes and MAFLD) and cardiovascular diseases. In addition, gut microbes regulate host glutamine metabolism through metabolites and signaling pathways, further affecting the disease process. Therapeutic strategies to target glutamine metabolism include inhibition of key enzymes or transporters, as well as exogenous glutamine supplementation. However, the effects of these strategies are context-dependent and need to be applied individually according to the specific pathological status of patients. Future research should focus on tissue-specific metabolic profiling, integrated multiomics analysis, and the development of combined treatment strategies to fully realize the potential of glutamine metabolism in disease treatment.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"166 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088751","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":"Gene-structured histology for deriving and predicting pancreatic cancer molecular subtypes","authors":"Alejandro Leyva, Abdul Rehman Akbar, Muhammad Khalid Khan Niazi","doi":"10.1038/s41392-026-03051-2","DOIUrl":"https://doi.org/10.1038/s41392-026-03051-2","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087703","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":"Multi-omics profiling reveals homologous recombination repair hyperactivation as a therapeutic vulnerability in neuroendocrine cervical carcinoma","authors":"Binhua Dong, Yue Wang, Yunna Qin, Lihua Chen, Yuxuan Huang, Ting Yang, Xianhua Liu, Xiaohong Chen, Yanlin Chen, Yanhua Lin, Saihua Zheng, Shuxia Xu, Xinyu Yao, Shiyin Chen, Yu Zhang, Ling Li, Xiaowen Pu, Juntao Yang, Pengming Sun","doi":"10.1038/s41392-026-02822-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02822-1","url":null,"abstract":"Neuroendocrine cervical carcinoma (NECC) is an aggressive and rare malignancy comprising 0.9–1.5% of cervical cancers. Its molecular basis remains poorly understood, limiting treatment options. A national multicenter cohort survival analysis showed that NECC patients had a 5.17-fold higher death risk than non-NECC patients and demonstrated broad chemotherapy resistance, which was further validated in both NECC cell lines and patient-derived organoids. To identify therapeutic targets, multi‑omics profiling of NECC tumors and matched normal adjacent tissues revealed pronounced DNA replication stress and hyperactivation of homologous recombination repair (HRR). These findings were validated in cells and patient-derived organoids using DR-GFP reporter and pRPA32 assays, suggesting that NECC may be susceptible to PARP inhibitor therapy. NECC cells exhibited moderate PARP inhibitor sensitivity, greater than that of resistant non‑NECC lines but less than that of highly sensitive A2780 cells. However, combining PARP inhibitors with cisplatin/carboplatin did not enhance efficacy, prompting the exploration of alternative combinatorial targets. Multi-omics analysis and in vitro validation identified Bloom syndrome helicase (BLM) as a key factor overexpressed in NECC that modulates PARP inhibitor sensitivity. Further in vitro and in vivo experiments confirmed that combining PARP and BLM inhibitors achieved potent anticancer effects. Mechanistically, cancer-associated fibroblasts (CAFs) infiltration in the tumor microenvironment upregulated the transcription factor E2F1 via IL6, with ChIP‒qPCR verifying that activated E2F1 directly binds the BLM promoter (hg38, chr15:90,715,346–90,717,346) to drive its expression, suppressing PARP inhibitor sensitivity. Our findings establish dual PARP and BLM inhibition as a promising therapeutic strategy for NECC by blocking HRR pathway compensation.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087747","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":"Chromatin accessibility in leukemia: mapping and the limits of reprogramming","authors":"Juan L. Coelho-Silva,Diego A. Pereira-Martins,João A. Machado-Neto","doi":"10.1038/s41392-026-03020-9","DOIUrl":"https://doi.org/10.1038/s41392-026-03020-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"480 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088752","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":"Vascular calcification: pathogenic mechanisms, signaling crosstalk and translational therapeutics","authors":"Rui Hua,Bao Qiao,Xuehao Liu,Bingchen Jiang,Jinlei Wu,Chuanxin Zhang,Han Liu,Bailu Wang,Shujian Wei,Yuguo Chen","doi":"10.1038/s41392-026-02884-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02884-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088772","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":"The gasdermin family: from pyroptosis mechanisms to therapeutic targets","authors":"Weilv Xu,Shiyang Liu,Zexu Yu,Jinhuang Shi,Yang Yang,Fushan Shi","doi":"10.1038/s41392-026-02867-2","DOIUrl":"https://doi.org/10.1038/s41392-026-02867-2","url":null,"abstract":"Abstract The gasdermin (GSDM) family of proteins has emerged as the central executioner of pyroptosis, a form of inflammatory cell death characterized by plasma membrane rupture and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). Emerging evidence indicates that GSDMs exert diverse functions in health and various disease contexts, which can be either dependent on or independent of pyroptosis, including facilitating mucus secretion, regulating bone resorption, and modulating mitochondrial metabolism. This review provides a comprehensive overview of the GSDM family, detailing the molecular mechanisms of activation, regulation, pore formation, cell rupture and membrane repair. We explored the extensive crosstalk between GSDMs and other cell death modalities, including apoptosis, necroptosis, NETosis, and PANoptosis. Furthermore, we systematically discuss GSDMs’ ‘double-edged sword’ roles in diverse pathologies, ranging from host defense in infectious diseases and chronic inflammation in autoimmune disorders to their complex, context-dependent function in cancer progression and immunity. Finally, we evaluate emerging therapeutic strategies, encompassing small-molecule inhibitors such as disulfiram (DSF), necrosulfonamide (NSA) and dimethyl fumarate (DMF), as well as novel material-based delivery systems. Collectively, these advances underscore the therapeutic potential of targeting GSDMs for precise clinical intervention to treat both inflammatory and non-inflammatory diseases, as well as to enhance cancer immunotherapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088753","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":"Same mutagenic insult, different destinies: genetic background directs cancer evolution","authors":"Seung-Jae Lee,Jaehoon Bae","doi":"10.1038/s41392-026-03069-6","DOIUrl":"https://doi.org/10.1038/s41392-026-03069-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088754","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":"Safety and efficacy of human gingiva-derived mesenchymal stem cells in patients with type 1 diabetes: a double-blind, randomized, placebo-controlled, phase 1 trial","authors":"Qi Tang, Li Zhou, Liwen Fan, Wei Zhang, Xixiang Tang, Donglan Zeng, Mei Li, Yanhua Zhu, Mengyin Cai, Jia Yuan, Zheng Chen, Song Guo Zheng, Yanming Chen","doi":"10.1038/s41392-026-03021-8","DOIUrl":"https://doi.org/10.1038/s41392-026-03021-8","url":null,"abstract":"Current therapies for type 1 diabetes mellitus (T1DM) rarely halt progressive β-cell function loss due to autoimmune attack. Human gingiva-derived mesenchymal stem cells (GMSCs) have been shown to have therapeutic effects on a variety of autoimmune diseases through their potent immunomodulatory capacity, but clinical evidence for these effects is lacking in patients with T1DM. Here, we performed a double-blind, randomized, placebo-controlled, phase 1 trial to evaluate the safety and efficacy of GMSC therapy in T1DM patients (ChiCTR1800018339). Patients received 4 intravenous injections of GMSCs (1.0 × 106/kg) or placebo at intervals of 3 weeks between each treatment in combination with routine insulin therapy during the entire trial. All 18 randomized patients completed the trial. At week 12, patients receiving GMSCs displayed improvements in residual β-cell function, as evaluated by C-peptide levels, along with a decrease in the requirement for daily insulin treatment. Remarkably, one patient who received GMSC therapy achieved insulin withdrawal after the first treatment. Moreover, both groups had equal glycemic control, and GMSC therapy was not associated with an increased risk of adverse events, including hypoglycemia. Mechanistically, peripheral exhausted CD8+ T-cell proportions were significantly increased, which is consistent with the results of single-cell sequencing and in vivo and in vitro experiments, suggesting that GMSCs potentially induce CD8+ T-cell exhaustion to alleviate β-cell autoimmune injury. Overall, this study is the first clinical trial evaluating the safety and therapeutic effect of GMSC therapy in T1DM patients, indicating that GMSCs might serve as a promising novel treatment option for T1DM.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087748","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":"Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.","authors":"Ze Xiang, Jiarui Li, Yunyang Xu, Chenhao Xu, Shuhui Li, Shusen Zheng, Zhe Yang, Xuyong Wei, Xiao Xu","doi":"10.1038/s41392-026-03059-8","DOIUrl":"10.1038/s41392-026-03059-8","url":null,"abstract":"<p><p>Cell differentiation, the process by which stem cells acquire specialized functions, underpins embryonic development, tissue homeostasis, and regeneration. This process is governed by evolutionarily conserved signaling pathways, including Wnt, Notch, Hedgehog, TGF-β, and Hippo, which integrate extracellular cues with intrinsic genetic programs to determine cell fate. Here, we provide a comprehensive overview of the molecular architecture of these pathways, spanning ligand-receptor interactions to downstream transcriptional regulation. We further highlight multilayered regulatory mechanisms such as epigenetic modifications, non-coding RNAs, feedback loops, and pathway crosstalk that fine-tune signaling outputs to ensure spatiotemporal precision in fate decisions. We also discuss how tissue-specific contexts and interactions among these pathways generate distinct differentiation outcomes in different organs and disease settings. Dysregulation of these networks contributes to diverse pathological states, driving uncontrolled proliferation in cancer, maladaptive remodeling in cardiovascular disease, neuronal loss in neurodegeneration, metabolic imbalance, digestive dysfunction, chronic inflammation in respiratory and autoimmune diseases, and skeletal disorders. Reflecting their clinical importance, we also summarize recent therapeutic advances, including small-molecule inhibitors, monoclonal antibodies, gene-based strategies, and pathway-modulating compounds, which target these pathways to restore normal cellular function. Particular attention is given to distinguishing preclinical findings from clinical applications and to the translational challenges of pathway-targeted therapies. Collectively, this review underscores the central role of differentiation-related signaling in health and disease and highlights emerging opportunities for therapeutic intervention.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115079","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":"Balancing the skin: antagonistic ubiquitin-like signaling pathways govern epidermal homeostasis.","authors":"Katrin Rietscher, Benjamin Klein","doi":"10.1038/s41392-026-02960-6","DOIUrl":"10.1038/s41392-026-02960-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082021","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}