Signal Transduction and Targeted Therapy最新文献

{"title":"A longevity-associated variant of the human BPIFB4 gene prevents diastolic dysfunction in progeria mice.","authors":"Yan Qiu,Monica Cattaneo,Anna Maciag,Annibale A Puca,Paolo Madeddu","doi":"10.1038/s41392-025-02416-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02416-3","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"39 1","pages":"314"},"PeriodicalIF":39.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189186","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":"Liquid biomarkers associate with TGF-β Type I receptor and hypoxia in kidney cancer.","authors":"Pramod Mallikarjuna,Cemal Erdem,Ruben Ilundain Beorlegui,Anders Larsson,Börje Ljungberg,Masood Kamali-Moghaddam,Maréne Landström","doi":"10.1038/s41392-025-02404-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02404-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":"309"},"PeriodicalIF":39.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140218","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":"Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy.","authors":"Byeongmin Park,Jiwoong Choi,Jae-Hyeon Lee,Yelee Kim,Woohyeong Lee,Ansoo Lee,In-Cheol Sun,Hong Yeol Yoon,Yongju Kim,Sun Hwa Kim,Yoosoo Yang,Kwangmeyung Kim,Jooho Park,Man Kyu Shim","doi":"10.1038/s41392-025-02405-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02405-6","url":null,"abstract":"Photodynamic therapy (PDT) induces tumor cell pyroptosis, a form of programmed cell death that triggers antitumor immunity. However, high glucose metabolism and hypoxic conditions in the tumor microenvironment (TME) limit PDT efficiency and impair effector cell function. Here, we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC; NanoTAC), derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinase II (HK2) and a photosensitizer via a biomarker-cleavable linker. In a triple-negative breast cancer (TNBC) model, NanoTAC initially silences PROTAC activity and accumulates in tumor regions, where it undergoes linker cleavage in response to enzymatic biomarkers. Upon photoirradiation, PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to drive the cancer-immunity cycle. Concurrently, targeted protein degradation (TPD) via PROTACs counteracts glucose and oxygen consumption in the TME, ultimately potentiating pyroptosis-mediated photoimmunotherapy. This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence. Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs, shedding light on strategies for more effective cancer immunotherapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"319 1","pages":"310"},"PeriodicalIF":39.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140217","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":"A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.","authors":"Zhiheng Rao,Zhichao Chen,Yuxuan Bao,Zhenzhen Lu,Yuli Tang,Jiamei Zhu,Jianjia Ma,Siyang Dong,Jiawei Shi,Suhui Sheng,Yajing Chen,Jiaojiao Wang,Alan Vengai Mukondiwa,Ziyue Li,Xulan Wang,Zibo Huang,Chi Li,Wumengwei Ding,Mengjie Chen,Ziyi Han,Cong Wang,Xuebo Pan,Xiaojie Wang,Hong Zhu,Li Lin,Zhifeng Huang,Weiqin Lu,Xiaokun Li,Yongde Luo","doi":"10.1038/s41392-025-02402-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02402-9","url":null,"abstract":"The heart, an organ with a continuously high demand for energy, inherently lacks substantial reserves. The precise mechanisms that prioritize energy allocation to cardiac mitochondria, ensuring steady-state ATP production amidst high-energy organs, remain poorly understood. Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21. We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux, arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency, directly impair cardiac energetic performance. Locally, this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways, along with hindered mitochondrial biogenesis, TCA cycle, ETC flow, and OXPHOS. Consequently, the heart shifts to a hypometabolic, glycolytic, and hypoenergy state, with a reduced capacity to cope with physiological stressors such as fasting, starvation, strenuous exercise, endurance training, and cold exposure, leading to a diminished heart rate, contractility, and hemodynamic stability. Pharmacological or genetic restoration of FGF21 ameliorates these defects, reenergizing stress-exhausted hearts. This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways. Disrupting cardiac LKB1 or mTOR pathways, akin to stalling mitochondrial energy conduits, obstructs the FGF21-governed cardiac energetic potential. Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21, which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency. This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"42 1","pages":"315"},"PeriodicalIF":39.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140221","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":"An aptamer-drug conjugate for promising cancer therapy with comprehensive evaluation from rodents to non-human primates.","authors":"Minhui Su,Yuan Liu,Hongxin Lin,Xiaoxing Wang,Danxia Ying,Lizhuan Zhang,Cai Yang,Mengyuan Jiang,Lujuan Xu,Xie Wang,Yang Sun,Haiyan Xu,Ziwen Zhang,Xiaojia Wang,Ting Fu,Sitao Xie,Jiaxuan He,Xiangsheng Liu,Weihong Tan","doi":"10.1038/s41392-025-02399-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02399-1","url":null,"abstract":"Aptamers serve as unique targeting ligands, making aptamer-drug conjugates (ApDCs) an attractive strategy for targeted cancer therapy. This study performs a comprehensive evaluation from rodents to non-human primates (NHP) of a protein tyrosine kinase 7 (PTK7)-targeted ApDC (Sgc8c-M) made by conjugating the potent antimitotic agent monomethyl auristatin E (MMAE) to the classic PTK7 aptamer Sgc8c. Efficacy studies in various cancer types with PTK7 overexpression showed that Sgc8c-M effectively induces sustained tumor regression in cell line-derived and patient-derived xenografts, outperforming unconjugated MMAE, the chemotherapy drug paclitaxel, and a PTK7-targeted antibody-drug conjugate. Pharmacokinetic (PK) studies in mice revealed that Sgc8c-M leads to rapid accumulation and sustained MMAE levels in tumors, along with fast clearance from plasma and normal tissues. Further study in rats confirmed rapid clearance across most organs and revealed that over 75% of MMAE was excreted through urine and feces within 24 h. Toxicokinetic (TK) assessments indicated comparable systemic drug exposure without accumulation for repeated doses compared to single administration. Toxicity evaluations showed that the therapeutic dose with high efficacy was safe and that the toxicity resulting from extremely high doses could be reversibly controlled. Encouraged by these findings, we evaluated PK/TK profiles and safety of Sgc8c-M in cynomolgus monkeys. Similar to PK/TK profiles observed in rats, Sgc8c-M demonstrated good dose-dependent drug exposure. It was, moreover, well tolerated in monkeys with no obvious accumulation following multiple administrations. These findings highlight the potential of Sgc8c-M as an effective antitumor agent and provide useful insights for the clinical translation of emerging ApDCs.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":"316"},"PeriodicalIF":39.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127077","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":"Ninjurin-1 mediates cell lysis and detrimental inflammation of PANoptosis during influenza A virus infection.","authors":"Yitian Xu,Ying Zheng,Yan Liu,Cheng Wei,Juan Ren,Wenting Zuo,Runqing Gu,Hongyu Liu,Xiaoyan Deng,Yaxue Liu,Xiao Shang,Weiwei Ge,Ziyao Li,Yijiao Huang,Di He,Xuhui Shen,Zeyi Wang,Chen Lyu,Zai Wang,Yuxian Mu,Zihuan Zhang,Hongping Wu,Haibo Li,Bin Cao","doi":"10.1038/s41392-025-02391-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02391-9","url":null,"abstract":"Influenza A virus (IAV) induces ZBP1-mediated PANoptosis, a form of lytic inflammatory cell death characterized by concurrent activation of the pyroptosis, necroptosis and apoptosis pathways. Ninjurin-1 (NINJ1) is a recently identified mediator of plasma membrane rupture but functions diversely in different types of cell death. However, little is known about the role of NINJ1 in IAV-induced PANoptosis and viral pneumonia. Here, we report that IAV infection triggered an increase in the expression of NINJ1, which then oligomerized and mediated cell lysis in infected macrophages. The deficiency of NINJ1 prevented plasma membrane rupture and the release of DAMPs and IL-1β without affecting the progression of cell death. Activation of any single PANoptosis pathway was sufficient to trigger the oligomerization of NINJ1 and robust cell lysis. Accordingly, only when all PANoptosis pathways were concurrently blocked could the oligomerization of NINJ1, cell death, and cell rupture be prevented. Ablation of NINJ1 in vivo also alleviated IAV-induced lung injury and mortality. Furthermore, we revealed an association between NINJ1 upregulation and poor outcomes in patients with COVID-19. Collectively, our findings indicate a pivotal role of NINJ1 in the immunopathology of IAV infection and its potential as a bioindicator of disease severity and prognosis in viral pneumonia and viral sepsis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":"307"},"PeriodicalIF":39.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116750","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":"Microbial metabolite facilitates virus control: inosine and T cells curb early-life influenza infection.","authors":"Lisa Sevenich,Thi Trang Le,Lukas F Mager","doi":"10.1038/s41392-025-02417-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02417-2","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"308"},"PeriodicalIF":39.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116749","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":"Spatiotemporal multi-omics analysis uncovers NAD-dependent immunosuppressive niche triggering early gastric cancer.","authors":"Pingting Gao,Chunman Zuo,Wei Yuan,Jiabin Cai,Xiaoqiang Chai,Ruijie Gong,Jia Yu,Lu Yao,Wei Su,Zuqiang Liu,Shengli Lin,Yun Wang,Mingyan Cai,Lili Ma,Quanlin Li,Pinghong Zhou","doi":"10.1038/s41392-025-02390-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02390-w","url":null,"abstract":"Understanding the cellular origins and early evolutionary dynamics that drive the initiation of carcinogenesis is critical to advancing early detection and prevention strategies. By characterizing key molecular, cellular and niche events at the precancerous tipping point of early gastric cancer (EGC), we aimed to develop more precise screening tools and design targeted interventions to prevent malignant transformation at this stage. We utilized our AI models to integrate spatial multimodal data from nine EGC endoscopic submucosal dissection (ESD) samples (covering sequential stages from normal to cancer), construct a spatial-temporal profile of disease progression, and identify a critical tipping point (PMC_P) characterized by an immune-suppressive microenvironment during early cancer development. At this stage, inflammatory pit mucous cells with stemness (PMC_2) interact with fibroblasts via NAMPT ⟶ ITGA5/ITGB1 and with macrophages via AREG ⟶ EGFR/ERBB2 signaling, fostering cancer initiation. We established gastric precancerous cell lines and organoids to demonstrate that NAMPT and AREG promote cellular proliferation in vitro. Furthermore, in the transgenic CEA-SV40 mouse model, targeting AREG and/or NAMPT disrupted key cell interactions, inhibited the JAK-STAT, MAPK, and NFκB pathways, and reduced PD-L1 expression, which was also confirmed by western blot in vitro. These interventions delayed disease progression, reversed the immunosuppressive microenvironment, and prevented malignant transformation. Clinical validation was conducted using endoscopically resected EGC specimens. Our study provides a precise spatiotemporal depiction of EGC development and identifies novel diagnostic markers and therapeutic targets for early intervention.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"87 1","pages":"313"},"PeriodicalIF":39.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103342","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":"Ultrasound activated herbal bio-heterojunctions for self-catalytic regulation and bacterial cuproptosis-like death in the treatment of implant infection.","authors":"Yan Yue,Shuoyuan Li,Qiang Su,Xufeng Wan,Qiaochu Li,Zhuang Zhang,Hong Xu,Fuyuan Zheng,Yangming Zhang,Le Tong,Jian Cao,Long Zhao,Xiaoting Chen,Qi Li,Yi Zeng,Haoyang Wang,Yi Deng,Zongke Zhou,Duan Wang","doi":"10.1038/s41392-025-02388-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02388-4","url":null,"abstract":"Conventional antibiotic strategies often fail to consistently suppress escaping planktonic bacteria and even induce antibiotic resistance, allowing implant-associated infections (IAIs) to persist. In this study, we demonstrated an antibiotic-free coating engineered with an herbal bioheterojunction featuring a shell-in-shell structure where Cu2O forms the core, strontium (Sr) is loaded in the inner shell, and curcumin (Cur) is nucleated in situ at the outer heterointerface (Cu2O-Sr/Cur). Ultrasound-triggered reactive oxygen species (ROS) generation by the outer heterostructure (Cu2O/Cur), coupled with Cu(I)-induced cuproptosis-like bacterial death, achieved antibacterial rates of 99.56% against S. aureus and 99.43% against E. coli. When ultrasonication ceases, the released Cu(I) undergoes disproportionation reactions to form Cu(II), which can chelate with Cur to form Cu-Cur metal complexes. These complexes exhibit enhanced antioxidative properties through self-catalytic regulation, the scavenging of ROS, and the activation of anti-inflammatory M2 macrophage phenotype. Moreover, strontium release from the inner shell simultaneously suppressed osteoclast activity and promoted osteogenesis, resulting in trabecular number and thickness increases of 129.03% and 56.71%, respectively, compared with those in control group. Therefore, our work establishes a sequential treatment strategy for the antibacterial properties and osteointegration ability of IAIs.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":"303"},"PeriodicalIF":39.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083389","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":"Rewiring interferon fate: a bidirectional strategy for immune homeostasis.","authors":"Ben Wielockx,Diego Rodriguez,Peter Mirtschink","doi":"10.1038/s41392-025-02393-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02393-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"28 1","pages":"297"},"PeriodicalIF":39.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083388","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}