Cell Death Discovery最新文献

{"title":"METTL3-mediated m6A modification of circCDKAL1 regulates macrophage M1 polarization and nasal epithelial cell barrier function in allergic rhinitis through IGF2BP2/JARID2/HMGB1 axis.","authors":"Jiabin Zhan, Dan Luo, Yunlong Fu, Yu Zhou, Rui Li, Xin Wei","doi":"10.1038/s41420-025-02710-7","DOIUrl":"10.1038/s41420-025-02710-7","url":null,"abstract":"<p><p>Allergic rhinitis (AR) is a chronic inflammatory disease that significantly impairs patients' quality of life, with CircCDKAL1 showing abnormal upregulation in AR patients, though its functional mechanisms remain unclear. In this study, we confirmed the identity of circCDKAL1 and its subcellular localization. Our findings revealed that circCDKAL1 expression was enhanced in samples of AR patients, AR mice and OVA-induced HNEpCs. Besides, circCDKAL1 silencing resulted in improvement of nasal mucosal epithelial barrier function/epithelial cell adhesion and promotion of macrophage M2 polarization in AR. Mechanistically, we discovered that circCDKAL1 was modified by m6A, which was mediated by METTL3. YTHDC1 promoted cytoplasmic output of m6A-modified circCDKAL1. In addition, circCDKAL1 destabilized JARID2 mRNA through interacting with IGF2BP2. Moreover, circCDKAL1 or HMGB1 silencing attenuated JARID2 silencing-mediated damages of epithelial cell adhesion and promotion of macrophage M1 polarization in OVA-induced HNEpCs. In conclusion, METTL3-mediated m6A modification of circCDKAL1, which was transferred from the nucleus to the cytoplasm by YTHDC1, promoted macrophage M1 polarization and impaired nasal mucosal epithelial barrier function/epithelial cell adhesion in AR through interacting with IGF2BP2 and regulating JARID2/HMGB1 axis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"417"},"PeriodicalIF":7.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis for the treatment of inflammatory disorders and kidney injury.","authors":"Yuting Ji, Shujing Du, Jingjing Li, Haikuo Ma, Xinhui Wang, Yongjin Hao, Zhanhui Li, Haohao Lu, Hao Liu, Chengkui Yang, Xiaohu Zhang, Sudan He","doi":"10.1038/s41420-025-02693-5","DOIUrl":"10.1038/s41420-025-02693-5","url":null,"abstract":"<p><p>Dysregulation of cell death plays a critical role in the onset and progression of numerous human diseases. Distinct forms of regulated cell death, such as necroptosis and ferroptosis, have been implicated in the pathogenesis of various conditions, including neurodegenerative disorders and acute kidney injury. Strategies that concurrently target both necroptosis and ferroptosis present significant potential for improving therapeutic outcomes. In this study, we identified Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis in both human and mouse species. Zharp1-163 effectively blocks ferroptosis by reducing reactive oxygen species (ROS) levels and inhibits necroptosis by potently and selectively targeting RIPK1 kinase activity. In vivo, Zharp1-163 markedly attenuated TNF-α-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Notably, Zharp1-163 significantly alleviated acute kidney injury associated with both necroptosis and ferroptosis in models induced by cisplatin treatment and ischemia-reperfusion. Collectively, our findings establish Zharp1-163 as a dual-action inhibitor capable of effectively suppressing both ferroptosis and necroptosis. These findings highlight its great potential in the treatment of diseases associated with these cell death pathways, such as kidney disease.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"413"},"PeriodicalIF":7.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron-responsive ZNF185 overexpression drives mitochondrial fission and endoplasmic reticulum stress via cytoskeletal remodeling in granulosa cells.","authors":"Zhaoyue Huang, Yang You, Qi Qiu, Nan Dong, Xinye Hu, Meihong Cai, Yaoqiu Wu, Chunwei Cao, Qingxue Zhang","doi":"10.1038/s41420-025-02719-y","DOIUrl":"10.1038/s41420-025-02719-y","url":null,"abstract":"<p><p>Ovarian endometrioma (OMA), an estrogen-dependent gynecological disorder, is characterized by the presence of abundant free iron resulting from recurrent hemorrhage of endometrial cells within the cyst, which adversely affects ovarian function. However, the underlying mechanisms through which iron overload impairs ovarian function remain unclear. In this study, we stimulated KGN cells with ferric ammonium citrate (FAC) in vitro and observed dose-dependent significant alterations, including decreased mitochondrial membrane potential, increased reactive oxygen species (ROS), decreased cell viability, and elevated apoptosis rates. RNA sequencing analysis of iron-overloaded KGN cells demonstrated significant upregulation of ZNF185 expression across multiple concentration gradients and treatment durations. ZNF185 overexpression was found to disrupt F-actin dynamics, triggering a cascade of cellular events including Drp1-mediated mitochondrial hyperfission, endoplasmic reticulum stress, and cytochrome C release, ultimately leading to granulosa cell apoptosis. Importantly, knockdown of ZNF185 was shown to preserve cytoskeletal integrity and attenuate apoptotic responses under conditions of iron overload. Our findings demonstrated that ZNF185 served as a novel iron-responsive regulator involved in iron overload-induced granulosa cell apoptosis. These results might provide potential therapeutic strategies for ovarian fertility preservation in OMA patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"414"},"PeriodicalIF":7.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role and clinical value of natriuretic peptide receptor family in malignant tumor.","authors":"Chuqi Quan, Weilin Shao, Yihao Yang, Qian Yao, Zuozhang Yang, Zhihong Yao","doi":"10.1038/s41420-025-02656-w","DOIUrl":"10.1038/s41420-025-02656-w","url":null,"abstract":"<p><p>The natriuretic peptide receptor (NPR) family (NPRA, NPRB, NPRC) regulates diverse physiological and pathological processes. Mounting evidence implicates NPRs as key regulators of oncogenesis, metastasis, and therapy resistance in multiple cancers. This review integrates current understanding of the distinct mechanisms by which NPR members contribute to cancer development and progression, explores their molecular underpinnings, and discusses translational potential and future directions. A central focus is the context-dependent functional duality of NPR signaling, where specific subtypes act as either oncogenic drivers or tumor suppressors depending on the malignancy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"412"},"PeriodicalIF":7.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HapA protease targets PAR-1/2 to modulate ERK signalling and reduce cancer cell viability.","authors":"David Tena-Chaves, Inês Pontes-Gomes, José Ángel Palomeque, Eric Toh, Palwasha Baryalai, Gabor Kadler, Reto A Schuepbach, Dorothea M Heuberger, Antoni Hurtado, Sun Nyunt Wai","doi":"10.1038/s41420-025-02691-7","DOIUrl":"10.1038/s41420-025-02691-7","url":null,"abstract":"<p><p>Recent studies reveal that Vibrio cholerae secretes virulence factors impacting host cell viability, though their effects on cancer cells remain unclear. However, the bacterial components and mechanisms influencing cancer cells remain largely unknown. This study investigated the effects of V. cholerae mutants lacking secreted proteins on carcinoma cells. We identified the hemagglutinin zinc-metalloprotease HapA as the main factor reducing cancer cell viability. HapA cleaves protease-activated receptors 1 and 2 on epithelial cancer cells at unique sites, unlike human proteases. This cleavage triggers an early and transient activation of the kinases MEK and ERK. Transient MEK and ERK activation initiates caspase 7, leading to apoptosis and reduced viability in epithelial cancer cells. Our findings underscore the significance of human protease-activated receptors as targets for bacterial protease HapA. Furthermore, we demonstrate that selective cleavage of PAR-1/2 by HapA adjusts MEK-ERK signalling dynamics, suggesting potential new avenues for the development of novel anticancer therapies. Understanding how pathogens like V. cholerae interact with cancer cells sheds light on potential mechanisms underlying cancer progression and suggests new therapeutic targets for cancer treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"415"},"PeriodicalIF":7.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-uniform impact of extracellular osmotic variations at subcellular level.","authors":"Pragya Singh, Aditya Mittal","doi":"10.1038/s41420-025-02703-6","DOIUrl":"10.1038/s41420-025-02703-6","url":null,"abstract":"<p><p>Osmotic perturbations, towards understanding basic cellular architectures and to alter cellular mechanics for various purposes, are widely utilized in cell biology. While osmotic perturbations are known to alter whole-cell morphology, their subcellular-level impacts remain poorly characterized. Here, we employ a novel quantitative imaging workflow to demonstrate that extracellular osmolarity induces organelle-specific redistribution patterns in adherent RAW264.7 macrophages, independent of whole-cell morphological changes. At the whole-cell level, we report a decrease in cellular pleomorphism (pixel-intensity-distribution-based heterogeneity) under non-isotonic conditions, with cell membrane and lysosomal pleomorphism decreasing as osmolarity decreases. Remarkably, osmolarity-induced variations observed at whole-cell level are translated to actin and tubulin variations only while nucleus, mitochondria, and endoplasmic reticulum are independent of the whole cell morphology alterations. However, there appears to be 'counterbalancing' of lateral polarity in the distributions of nucleus and endoplasmic reticulum in hypo-osmotic conditions. This work promises to be a key contribution towards understanding cellular architectures.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"410"},"PeriodicalIF":7.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic dysregulation in pulmonary fibrosis: insights into amino acid contributions and therapeutic potential.","authors":"Hongyu Zheng, Lei Zhang, Congjian Wang, Yi Wang, Chenxi Zeng","doi":"10.1038/s41420-025-02715-2","DOIUrl":"10.1038/s41420-025-02715-2","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disease characterized by excessive extracellular matrix deposition and fibroblast activation. Emerging evidence suggests that amino acid metabolism plays a crucial role in the pathogenesis of pulmonary fibrosis. Key amino acids, including arginine, proline, and glutamine, contribute to the regulation of fibroblast activity and collagen synthesis, all of which are essential for fibrotic progression. Studies in experimental models of pulmonary fibrosis have demonstrated significant metabolic dysregulation, further highlighting its relevance in disease development. Moreover, targeting amino acid metabolism has emerged as a promising therapeutic strategy, with novel drugs and interventions designed to modulate metabolic pathways showing potential in preclinical and clinical studies. This review explores the intricate interplay between amino acid metabolism and pulmonary fibrosis, discusses its implications for disease progression, and evaluates the therapeutic prospects of metabolic interventions in IPF management. Understanding these metabolic mechanisms may pave the way for more effective and personalized treatment strategies for IPF.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"411"},"PeriodicalIF":7.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ioning out glioblastoma: ferroptosis mechanisms and therapeutic frontiers.","authors":"Hetong Sun, Jiayu Zhang, Henan Qi, Dandan Jiang, Caofang Hu, Chengyu Mao, Wei Liu, Hongzhao Qi, Jinbao Zong","doi":"10.1038/s41420-025-02711-6","DOIUrl":"10.1038/s41420-025-02711-6","url":null,"abstract":"<p><p>Glioblastoma (GBM) (IDH-wildtype), the most prevalent and malignant primary brain tumor in adults, continues to pose a major therapeutic challenge in neuro-oncology. Despite significant advancements in cancer diagnosis and treatment technologies, conventional therapies remain largely ineffective against this tumor, urgently necessitating breakthrough treatment strategies. This comprehensive review critically examines recent advances in targeting ferroptosis, an iron-dependent form of non-apoptotic cell death mediated through reactive oxygen species (ROS) accumulation and lipid membrane peroxidation, for therapeutic intervention in GBM. The key aspects analyzed encompass the unique molecular mechanisms that distinguish ferroptosis from apoptosis and necrosis, along with its regulatory networks in GBM. The analysis also explores the therapeutic potential of targeting critical ferroptosis pathways, including dysregulated iron metabolism, impaired antioxidant defenses, and abnormal lipid peroxidation. Additionally, it examines the synergistic effects and molecular basis of combining ferroptosis inducers with chemo-radiotherapy or immunotherapy. Finally, the study highlights innovative applications of nano-drug delivery technologies in overcoming blood-brain barrier (BBB) limitations and enhancing the precision of ferroptosis-targeted therapy. Notably, this review provides a comprehensive analysis of the interplay between ferroptosis regulation and the tumor immune microenvironment, highlighting a promising 'ferroptosis-immunotherapy' combination strategy with clinical translation potential for GBM treatment. While challenges persist regarding incomplete understanding of regulatory networks and nanocarrier biosafety issues, this review not only provides a theoretical framework for comprehending ferroptosis-mediated anti-GBM mechanisms but also outlines future research directions, including in-depth dissection of ferroptosis signaling hubs, development of intelligent nano-delivery systems, and establishment of preclinical safety evaluation protocols. These findings are expected to provide revolutionary therapeutic targets for achieving precision treatment of GBM.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"407"},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Modulatory role of radioprotective 105 in mitigating oxidative stress and ferroptosis via the HO-1/SLC7A11/GPX4 axis in sepsis-mediated renal injury.","authors":"Hong Duo, Yanwei Yang, Jun Luo, Yumeng Cao, Qian Liu, Jiarui Zhang, Siqi Du, Jian You, Guqin Zhang, Qifa Ye, Huaqin Pan","doi":"10.1038/s41420-025-02668-6","DOIUrl":"10.1038/s41420-025-02668-6","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"409"},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: N4BP3 facilitates NOD2-MAPK/NF-κB pathway in inflammatory bowel disease through mediating K63-linked RIPK2 ubiquitination.","authors":"Wang Jiang, Yan Zhao, Min Han, Jiafan Xu, Kun Chen, Yi Liang, Jie Yin, Jinyue Hu, Yueming Shen","doi":"10.1038/s41420-025-02574-x","DOIUrl":"10.1038/s41420-025-02574-x","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"408"},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}