Signal Transduction and Targeted Therapy最新文献

{"title":"Branched-chain amino acids alleviate sepsis-induced myocardial dysfunction via inhibition of protein tyrosine phosphatase-6","authors":"Shu-Rui Pang, Yu-Tong Zhu, Hou-Zao Chen, Jian-Fei Pei, De-Pei Liu","doi":"10.1038/s41392-025-02224-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02224-9","url":null,"abstract":"<p><b>Dear editor</b>,</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"57 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889424","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":"Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer","authors":"Chen Wei, Kun Liao, Hao-Jie Chen, Zi-Xuan Xiao, Qi Meng, Ze-Kun Liu, Yun-Xin Lu, Hui Sheng, Hai-Yu Mo, Qi-Nian Wu, Yi Han, Zhao-Lei Zeng, Xin-Yuan Guan, Hui-Yan Luo, Huai-Qiang Ju, Rui-Hua Xu","doi":"10.1038/s41392-025-02221-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02221-y","url":null,"abstract":"<p>Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal cancer growth. Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880653","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":"N-deglycosylation targeting chimera (DGlyTAC): a strategy for immune checkpoint proteins inactivation by specifically removing N-glycan","authors":"Li Li, Jiajia Wu, Weiqian Cao, Wei Zhang, Qi Wu, Yaxu Li, Yanrong Yang, Zezhi Shan, Zening Zheng, Xin Ge, Liang Lin, Ping Wang","doi":"10.1038/s41392-025-02219-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02219-6","url":null,"abstract":"<p>Among the leading methods for triggering therapeutic anti-cancer immunity is the inhibition of immune checkpoint pathways. N-glycosylation is found to be essential for the function of various immune checkpoint proteins, playing a critical role in their stability and interaction with immune cells. Removing the N-glycans of these proteins seems to be an alternative therapy, but there is a lack of a de-N-glycosylation technique for target protein specificity, which limits its clinical application. Here, we developed a novel technique for specifically removing N-glycans from a target protein on the cell surface, named deglycosylation targeting chimera (DGlyTAC), which employs a fusing protein consisting of Peptide-N-glycosidase F (PNGF) and target-specific nanobody/affibody (Nb/Af). The DGlyTAC technique was developed to target a range of glycosylated surface proteins, especially these immune checkpoints—CD24, CD47, and PD-L1, which minimally affected the overall N-glycosylation landscape and the N-glycosylation of other representative membrane proteins, ensuring high specificity and minimal off-target effects. Importantly, DGlyTAC technique was successfully applied to lead inactivation of these immune checkpoints, especially PD-L1, and showed more potential in cancer immunotherapy than inhibitors. Finally, PD-L1 targeted DGlyTAC showed therapeutic effects on several tumors in vivo, even better than PD-L1 antibody. Overall, we created a novel target-specific N-glysocylation erasing technique that establishes a modular strategy for directing membrane proteins inactivation, with broad implications on tumor immune therapeutics.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880651","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":"You are what you eat: metabolic recycling of phagocytosed bacteria modulates macrophage immunity","authors":"Syamantak Basu, Manuela Rossol","doi":"10.1038/s41392-025-02222-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02222-x","url":null,"abstract":"<p>In a recent study published in <i>Nature</i>, Lesbats et al.¹ show that phagocytosed bacteria can be recycled by macrophages to serve as an alternative nutrient source. Bacterial cAMP was identified as a signal for macrophages to differentiate between dead and live bacteria and to adjust the inflammatory response accordingly.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"35 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880654","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":"Diabetic neuropathy: cutting-edge research and future directions","authors":"Yang Yang, Bing Zhao, Yuanzhe Wang, Hongli Lan, Xinyu Liu, Yue Hu, Peng Cao","doi":"10.1038/s41392-025-02175-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02175-1","url":null,"abstract":"<p>Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"70 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872169","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":"STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic degradation","authors":"Xiaohong Wang, Tao Chen, Sizhe Chen, Jie Zhang, Liangyu Cai, Changhao Liu, Yujie Zhang, Xiao Wu, Na Li, Zhiyong Ma, Lei Cao, Qian Li, Chenghu Guo, Qiming Deng, Wenqian Qi, Yonghao Hou, Ruiqing Ren, Wenhai Sui, Haonan Zheng, Yun Zhang, Meng Zhang, Cheng Zhang","doi":"10.1038/s41392-025-02216-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02216-9","url":null,"abstract":"<p>Despite advancements in interventional coronary reperfusion technologies following myocardial infarction, a notable portion of patients continue to experience elevated mortality rates as a result of myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury is crucial for devising strategies to minimize myocardial damage and enhance patient survival. Here, it is discovered that during MI/R, double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal accumulates, accompanied by high rates of myocardial ferroptosis. The specific deletion of <i>cgas</i> or <i>Sting</i> in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis and I/R injury. Conversely, activation of STING exacerbates ferroptosis and I/R injury. Mechanistically, STING directly targets glutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes and lysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking the STING-GPX4 interaction through mutations in <i>T</i>267 of STING or <i>N</i>146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4 administration alleviates ferroptosis induced by STING, resulting in enhanced cardiac functional recovery from MI/R injury. Additionally, the inhibition of STING by H-151 stabilizes GPX4 to reverse GPX4-induced ferroptosis and alleviate MI/R injury. Collectively, a novel autophagy-dependent ferroptosis mechanism is identified in this study. Specifically, STING autophagy induced by anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseases associated with I/R.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"48 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872172","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":"A20 attenuates oxidized self-DNA-mediated inflammation in acute kidney injury","authors":"Hanwen Li, Yongyao Wu, Lisha Xiang, Qing Zhao, Lu Liu, Zhixiong Zhu, Weimin Lin, Zhan Li, Yang Yang, Yiting Ze, Lulu Zhang, Ping Fu, Yingqiang Guo, Ping Zhang, Bin Shao","doi":"10.1038/s41392-025-02194-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02194-y","url":null,"abstract":"<p>The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis, but its role in self-DNA-mediated inflammation in acute kidney injury (AKI) is not well understood. Here, our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients. This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome. While inhibition of the STING pathway only slightly attenuates AKI progression, suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice. Subsequently, we found that <i>Tnfaip3</i> (encoding A20) is significantly upregulated following oxidized self-DNA treatment. A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis. Moreover, A20-derived peptide (P-II) also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice. Mechanistically, A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome. A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7. Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex. Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models. This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"41 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872224","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":"Bio-barrier-adaptable biomimetic nanomedicines combined with ultrasound for enhanced cancer therapy","authors":"Juan Guo, Xueting Pan, Qingyuan Wu, Ping Li, Chaohui Wang, Shuang Liu, Haoyuan Zhang, Zezhong Huang, Xiaozhou Mou, Huiyu Liu, Jiajia Xue","doi":"10.1038/s41392-025-02217-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02217-8","url":null,"abstract":"<p>Addressing the critical biological barriers of targeted accumulation and deep tumor penetration remains essential for the clinical translation of nanomedicines. However, existing nanomedicines often face challenges during in vivo transportation, including immune clearance, tumor microenvironmental barriers, and limited vascular permeability, which collectively reduce drug delivery efficiency and compromise therapeutic efficacy. Here, we present a bio-barrier-adaptable biomimetic nanoplatform, MSF@CCM, which integrates a mesoporous silica-loaded iron oxyhydroxide (MSF) core camouflaged with a homologous membrane. This design conferred dual functionality: (1) enhanced tumor accumulation and immune evasion by exploiting homologous cell-cell interactions and mimicking “self” markers, thereby effectively bypassing macrophage clearance and surpassing the limitations of traditional targeted drug delivery; and (2) amplified ultrasound (US)-mediated intratumoral penetration. The MSF core, with its unique porous structure and rough surface, significantly enhanced US cavitation effects, transiently disrupting tumor vasculature and facilitating deep penetration of nanomedicines. Upon US triggering, MSF@CCM effectively disrupted intracellular redox homeostasis, potently inducing ferroptosis via lipid peroxidation accumulation, mitochondrial morphological changes, and decreased key protein expression. This combined therapeutic strategy achieved a remarkable 96.5% tumor growth inhibition in vivo while maintaining favorable biocompatibility. Our findings establish a novel paradigm for overcoming multidimensional bio-barriers through biohybrid engineering and physical energy synergy, offering a promising modality for enhanced cancer therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872165","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":"Tumor immunology: a short IL18 cleavage product promotes cancer immunosurveillance","authors":"Emma Guilbaud, Lorenzo Galluzzi","doi":"10.1038/s41392-025-02213-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02213-y","url":null,"abstract":"<p>In a recent study published in <i>Nature Immunology</i>, Shen et al. have proposed that the caspase 3 (CASP3)-dependent cleavage of interleukin 18 (IL18) in malignant cells exposed to apoptotic inducers generates a short IL18 fragment that operates intracellularly to promote the secretion of IFN-stimulated gene 15 (ISG15) ubiquitin-like modifier, culminating with the recruitment of natural killer (NK) cells to the tumor microenvironment in support of cancer immunosurveillance.¹ While these findings delineate a novel signaling pathway linking atypical proteolytic processing of IL18 by malignant cells to anticancer immunity, the actual implication of CASP3 in such a signal transduction cascade remains unclear.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862181","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":"Rapavir, a novel inhibitor of sodium taurocholate cotransporting polypeptide, potently blocks hepatitis B virus entry","authors":"Jia He, Haibo Yu, Kunling Song, Ailong Huang, Yongjun Dang, Juan Chen, Zufeng Guo","doi":"10.1038/s41392-025-02214-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02214-x","url":null,"abstract":"<p><b>Dear Editor</b>,</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862194","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}