Signal Transduction and Targeted Therapy最新文献

{"title":"CAR T cells for HLA desensitization: a new era in kidney transplantation.","authors":"Peter R Mertens, Eugen Feist, Dimitrios Mougiakakos","doi":"10.1038/s41392-026-02989-7","DOIUrl":"10.1038/s41392-026-02989-7","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/PMC13623966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081995","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":"Transcriptional modulation of β-Secretase ameliorates amyloid pathology and cognitive deficits in Alzheimer's disease models.","authors":"Jinsu Park, Han-Gyu Bae, Yoonsuk Cho, Seung Hyun Baek, Dong-Gyu Jo","doi":"10.1038/s41392-026-02957-1","DOIUrl":"10.1038/s41392-026-02957-1","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/PMC13623964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081955","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":"Transcriptional intermediary factor 1 gamma-based multitarget gene therapeutic strategy for triple-negative breast cancer.","authors":"Hyomin Park, Tae Yoon Kim, Hyunji Yun, Areum Cha, Dodam Moon, Eugene Yun, Youngmin Kim, Seock-Ah Im, Dae-Won Lee, Changhee Park, Hong-Kyu Kim, Han-Byoel Lee, Jaewon Lee, Nam-Joon Cho, Eun Ju Lee, Hyo-Soo Kim","doi":"10.1038/s41392-026-02977-x","DOIUrl":"10.1038/s41392-026-02977-x","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. A multitarget gene therapy was developed and validated to overcome molecular heterogeneity and compensatory survival signaling in TNBC. A codon-optimized human transcriptional intermediary factor 1 gamma (opti-hTIF1γ) gene therapy was evaluated in ex vivo-cultured patient biopsy tissues and in orthotopic and mammary intraductal mouse models, and the underlying mechanisms were investigated using pathway and immune-functional analyses. Ex vivo findings were further validated using patient-derived cells and complementary mechanistic studies, including ubiquitination assays, chromatin immunoprecipitation, and functional macrophage coculture analyses, to define the molecular basis of TIF1γ-mediated antitumor activity. Transduction of opti-hTIF1γ to ex vivo-cultured biopsy tissues from TNBC patients suppressed epithelial-to-mesenchymal transition and proliferation while inducing apoptosis. In orthotopic and mammary intraductal mouse models, opti-hTIF1γ effectively suppressed tumor growth and lung metastasis. Mechanistically, opti-hTIF1γ inhibits β-catenin via ubiquitination-dependent degradation and inhibits the SMAD-dependent TGFβ pathway by binding to SMAD2/3. In parallel, it suppresses the SMAD-independent TGFβ pathway via ubiquitination and caspase-3-associated degradation of STAT3, leading to the inhibition of TAK1. Furthermore, opti-hTIF1γ downregulates STAT3-dependent immune modulators such as CD47 and CXCL5 in TNBC, enhancing macrophage phagocytosis. These findings position opti-hTIF1γ as a promising multitarget gene therapeutic strategy for TNBC through concurrent suppression of tumorigenic signaling and reprogramming of the immune landscape.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075828","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":"Polymeric alpha-1 antitrypsin perturbs Paneth cell proteostasis and exacerbates intestinal inflammation.","authors":"Francesco Annunziata, Felipe Dos Santos Matos, Irene Relvini, Jing Lu, Giovanna Federico, Claudia D'Agostino, Valentina Schiano, Veronica Maffia, Bruno Maria Custode, Gaetano Raiola, Barbara De Marino, Rossella De Cegli, Eugenio Del Prete, Elena Polishchuk, Carmen Ambrosio, Debora Compare, Gerardo Nardone, Francesco Neri, Nunzia Pastore","doi":"10.1038/s41392-026-02925-9","DOIUrl":"10.1038/s41392-026-02925-9","url":null,"abstract":"<p><p>Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that protects tissue from neutrophil elastase and other proteases, particularly in the lung. Mutations in SERPINA1, including the Z mutation, lead to AAT deficiency (AATD), characterized by reduced circulating AAT and increased risk of pulmonary emphysema, liver cirrhosis, and hepatocellular carcinoma. Beyond these well-characterized manifestations, AATD has been associated with panniculitis, rheumatoid arthritis, and glomerulonephritis. Emerging evidence has also suggested a link between AATD and inflammatory bowel diseases (IBDs), although experimental validation is lacking. In this study, we demonstrate that PiZ transgenic mice expressing the polymer-forming ATZ display increased susceptibility to dextran sodium sulfate (DSS)-induced colitis, accompanied by marked Paneth cell abnormalities. The accumulation of polymeric ATZ in Paneth cells is associated with the endoplasmic reticulum (ER) stress response, impaired lysosomal clearance, altered association of Lysozyme-1 (Lyz1) with LC3-containing compartments, and increased Lyz1 secretion. These intestinal alterations were accompanied by changes in microbiota composition, whereas DSS exposure and exogenous lysozyme administration were associated with aggravated intestinal and hepatic pathology. Pharmacological inhibition of ER stress restored crypt homeostasis and normalized Lyz1 secretion. Human Pi*ZZ iPSC-derived intestinal organoids similarly showed ATZ polymer accumulation in secretory epithelial cells and transcriptional alterations involving ER protein processing and epithelial homeostasis. In addition, polymeric ATZ was detected in ileal crypts from a single individual with AATD and intestinal disease. Together, our data reveal a Paneth cell-intrinsic ER stress mechanism linking ATZ accumulation to gut epithelial dysfunction, highlighting a previously underexplored role of the gut-liver axis in AATD.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075770","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":"Transketolase-like 1 potentiates PD-1 blockade in hepatocellular carcinoma by glycolysis to prime dendritic cell lactylation.","authors":"Hengsong Cao, Tian Huang, Yue Chai, Zhengqing Lu, Shipeng Dai, Danyang Xu, Yanshu He, Na Yu, Yuliang Wang, Ziyuan Liu, Yidong Xia, Jie Zhao, Hongyu Wang, Dawei Rong, Yuchen Xie, Chongyu Wang, Pengyu Chen, Juyue Zhou, Li Liu, Zhuozheng Li, Hanyuan Liu, Xiao Li, Xuehao Wang, Weiwei Tang, Yongxiang Xia","doi":"10.1038/s41392-026-02875-2","DOIUrl":"10.1038/s41392-026-02875-2","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) exhibits a suboptimal response to immune checkpoint blockade (ICB) therapy; to overcome this resistance, we aimed to delineate key immune resistance factors via multi-omics analysis, develop strategies to block their immunosuppressive axes, and engineer a targeted nanosystem to enhance immunotherapy efficacy against PD-1 resistance in HCC. Using transcriptomic and proteomic data from anti-PD-1-treated HCC patients, along with functional validation in murine models and mechanistic molecular and cell biology studies, we identified transketolase-like 1 (TKTL1) as a dual-nature biomarker where overexpression predicted poor baseline prognosis yet enhanced response to ICB. Mechanistically, TKTL1 diverts glucose flux into glycolysis rather than pentose phosphate pathway (PPP), recruiting USP9X to deubiquitinate and stabilize HIF-1α, which upregulates HK2 to amplify glycolytic output and lactate accumulation. This metabolic rewiring orchestrates dual immunosuppressive circuits through HIF-1α-driven CCL4 secretion recruiting PD-L1^high dendritic cells (DCs), coupled with lactate-induced TRIM28^K408 lactylation that stabilizes PD-L1 by blocking ubiquitin-mediated degradation. We engineered a hepatoma-membrane-coated MnO₂ nanosystem (CQLH) co-delivering a TKTL1 inhibitor and lactate oxidase, which disrupted the TKTL1-HIF-1α-HK2 axis, depleted lactate, and reprogrammed the tumor microenvironment, thereby enhanced anti-PD-1 therapy to suppress tumor growth, especially in TKTL1^high tumors. These findings define a critical \"TKTL1-glycolysis-lactate-DC\" axis driving anti-PD-1 sensitivity in HCC, position TKTL1 as both a potential biomarker for ICB response and a tractable therapeutic target, and demonstrate that the targeted CQLH nanosystem overcomes resistance and enhances anti-PD-1 efficacy, offering a precision immunotherapeutic strategy for TKTL1^high HCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070115","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":"Inotodiol prevents age-related muscle wasting by restoring mitochondrial function through liver X receptor beta signaling.","authors":"Chang-Lim You, Ju-Hyeon Bae, Yideul Jeong, Young-Eun Leem, June Kim, Jeongmin Park, Tuan Anh Vuong, Jiwoong Jang, Sanghee Park, Young-Sam Lee, Moongi Ji, Man-Jeong Paik, Il-Young Kim, Sang-Jin Lee, Gyu-Un Bae, Jong-Sun Kang","doi":"10.1038/s41392-026-02935-7","DOIUrl":"10.1038/s41392-026-02935-7","url":null,"abstract":"<p><p>Sarcopenia is characterized by a progressive decline in muscle mass and strength and represents a major contributor to increased mortality in the elderly population. Mitochondrial dysfunction, which leads to impaired energy metabolism and elevated oxidative stress, is a key driver of muscle wasting and associated metabolic disorders. Thus, mitochondrial targeting is a promising strategy for combating sarcopenia. In this study, we investigated the therapeutic potential of the mycosterol inotodiol (Ino) in mitigating age-related muscle wasting and metabolic dysfunction. Ino treatment significantly improved muscle mass and function in aged mice and prevented dexamethasone (DEX)-induced muscle atrophy. Ino enhanced mitochondrial function and restored muscle metabolism, as evidenced by increased mitochondrial content, elevated oxidative capacity, reduced lipid accumulation, and decreased oxidative stress. In addition, Ino attenuated palmitic acid (PA)-induced lipotoxicity in muscle cells by restoring lipid metabolism. Further investigation revealed that Ino activates liver X receptor β (LXRβ) and promotes its interaction with peroxisome proliferator-activated receptor δ (PPARδ), thereby increasing sirtuin 3 (Sirt3) transcription. Consequently, Ino activates the LXRβ/SIRT3/peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) signaling pathway, a central regulator of mitochondrial function and metabolic homeostasis. Collectively, these findings identify Ino as a promising therapeutic candidate for preserving mitochondrial function and alleviating age-associated muscle dysfunction.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040486","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":"Keeping forks in the loop: how chromatin architecture shields stalled replication forks.","authors":"Nagham Ghaddar, Jessica A Downs","doi":"10.1038/s41392-026-02992-y","DOIUrl":"10.1038/s41392-026-02992-y","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040495","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":"Artificial intelligence in biomarker discovery for diseases: diagnostic and therapeutic prospects.","authors":"Rasit Dinc, Nurittin Ardic","doi":"10.1038/s41392-026-02946-4","DOIUrl":"10.1038/s41392-026-02946-4","url":null,"abstract":"<p><p>Biomarkers are central to modern diagnostics and therapeutics, yet traditional discovery approaches suffer from single-modality analyses, weak mechanistic foundations, and low reproducibility. Artificial intelligence (AI) enables the integration of complex multimodal biomedical data, but the translation of AI-derived biomarkers into clinical applications remains inconsistent. This review examines how AI reshapes biomarker discovery across diseases, focusing on biological mechanisms, validation requirements, and therapeutic integration. We synthesize evidence across molecular, cellular, imaging, and digital biomarker approaches, evaluating AI methodologies including classical machine learning, deep learning, graph-based models, foundation models, and causal inference. Findings are organized using a pipeline framework encompassing discovery, external validation, robustness testing, clinical utility, and deployment. AI enables identification of multiscale signatures reflecting cellular programs, tissue remodeling, and disease trajectories. However, many biomarkers fail external validation. Biologically grounded approaches using network-based modeling, spatial profiling, and mechanistic constraints improve interpretability and therapeutic relevance in oncology, cardiovascular disease, neurodegeneration, and metabolic diseases. Validation frameworks with decision curve analysis and prospective evaluation are necessary to demonstrate clinical utility beyond predictive accuracy. AI's impact will depend on integration into rigorous validation and therapeutic pathways. By transitioning from correlational pattern recognition to mechanistically informed, clinically evaluated systems, AI can support next-generation precision diagnostics and targeted interventions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040506","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":"RNA therapeutics: current status and future directions.","authors":"Barbara Yang, Melina J Sedano, Karla Perez, Mahalakshmi Vijayaraghavan, Victoria A Reid, Murali M Yallapu, Subhash C Chauhan, Subramanian Dhandayuthapani, Enrique I Ramos, Shrikanth S Gadad","doi":"10.1038/s41392-026-03032-5","DOIUrl":"10.1038/s41392-026-03032-5","url":null,"abstract":"<p><p>RNA-based therapeutics have enabled drug discovery and design by introducing a fundamentally different perspective from conventional therapeutics. RNAs are not only the upstream molecules of proteins (coding) but also functional components of an extensive and intricate regulatory network (noncoding) that helps govern biological processes and mechanisms. Recent advances in functional genomics have accelerated the identification of functional RNAs with well-defined roles and their use in diagnostic and therapeutic approaches, which was previously challenging. RNA molecules can dynamically regulate gene function through their sequence and/or structure. Thus, RNA therapeutics offer distinct strategies for both loss- and gain-of-function interventions. This review focuses on druggable functional RNAs and discusses current and emerging technologies, as well as the scope for their potential clinical utility and targeted treatment. It also highlights the most studied optimization strategies and delivery systems designed to enhance the efficacy and tissue-specific delivery of RNA therapeutics to improve clinical outcomes. Finally, we offer our understanding and perspective on the field. Recent developments in enhancing the stability of these molecules in vivo have further improved the therapeutic potential of RNA-based approaches.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040476","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":"Inhibition of USP2 suppresses pathological pexophagy and rescues PEX1-deficient peroxisome biogenesis disorder.","authors":"Yong Hwan Kim, Doo Sin Jo, Ae-Kyeong Kim, Kyu Sun Lee, Dong-Hyung Cho","doi":"10.1038/s41392-026-02882-3","DOIUrl":"10.1038/s41392-026-02882-3","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031363","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}