Cell Death Discovery最新文献

{"title":"Correction: Let-7b-5p inhibits breast cancer cell growth and metastasis via repression of hexokinase 2-mediated aerobic glycolysis.","authors":"Ling Li, Xiujuan Zhang, Yanni Lin, Xinxin Ren, Tian Xie, Jing Lin, Shumeng Wu, Qinong Ye","doi":"10.1038/s41420-026-03069-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03069-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763689","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":"Identification and molecular typing of disulfidptosis-related biomarkers in anaplastic thyroid carcinoma.","authors":"Weidong Teng, Yawen Guo, Lingling Ding, Aoni Zhou, Yehao Guo, Jiantong He, Lirong Zhang, Haolan Yu, Zekai Tao, Jiafeng Wang, Jiajie Xu, Zhuo Tan, Liehao Jiang","doi":"10.1038/s41420-026-03089-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03089-9","url":null,"abstract":"<p><p>Increasing evidence suggests that disulfidptosis plays a crucial role in tumorigenesis and progression. This study aimed to identify biomarkers closely associated with disulfidptosis in anaplastic thyroid carcinoma (ATC). Utilizing ATC-related datasets (GSE65144, GSE9115, GSE27155, and GSE53072) in conjunction with disulfide bond-related genes (DRGs) identified in the literature, differentially expressed genes (DEGs) were screened from the GSE65144 and GSE9115 datasets. A total of 113 common DEGs were identified through cross-sectional analysis. Weighted gene co-expression network analysis (WGCNA) was employed to screen genes related to disulfidptosis and ATC, and five biomarkers-ATP1B3, TFF3, LGALS1, ADAM12, and COL1A2-were identified using machine learning algorithms. A nomogram model constructed based on these markers demonstrated high accuracy. In vitro validation revealed that ATP1B3 knockdown significantly inhibited tumor growth, indicating its potential anti-ATC activity. Furthermore, laser confocal microscopy, flow cytometry, and other experimental methods suggested a correlation between ATP1B3 and disulfidptosis. These findings highlight ATP1B3, TFF3, LGALS1, ADAM12, and COL1A2 as potential disulfidptosis-related biomarkers in ATC. This study provides a theoretical foundation for understanding the role of disulfidptosis in ATC pathogenesis and suggests that ATP1B3 may serve as a promising therapeutic target.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The iron-energy metabolism axis in Alzheimer's pathogenesis: from mechanisms to interventions.","authors":"Zhenyou Zou, Jia Chen, Jing Li, Yongfeng Chen","doi":"10.1038/s41420-026-03034-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03034-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder with a complex, multifactorial pathogenesis. Growing evidence implicates disturbances in cellular energy metabolism and iron dyshomeostasis as interlinked contributors to pathology. Within this framework, iron accumulation may act as an upstream regulator in certain contexts and stages, while in others it emerges downstream and amplifies ongoing injury. As iron is an essential cofactor for mitochondrial respiration and the tricarboxylic acid cycle, iron imbalance can compromise ATP production and disrupt glucose metabolism, exacerbating neuronal energy deficits. The interplay among iron accumulation, oxidative stress, and neuroinflammation can create vicious cycles that reprogram cellular metabolism and disrupt the critical metabolic coupling between neurons and glial cells. This review synthesizes recent advances in understanding the iron-energy metabolism axis in AD, delineates mechanisms by which iron imbalance precipitates mitochondrial dysfunction and glucose metabolic impairments, and evaluates how these deficits synergize with neuroinflammation and proteinopathy across disease stages. Finally, we appraise emerging therapeutic strategies targeting iron overload and metabolic pathways, discuss their stage-dependent risks and benefits, and outline the need for biomarker-guided approaches to optimize patient selection and treatment timing.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation.","authors":"Jing Jia, Kangkang Ji, Yong Zhou, Yang Huang, Ang Li, Fan Ye, Wen Huang, Fang Chen, Guoyuan Lu","doi":"10.1038/s41420-026-03113-y","DOIUrl":"https://doi.org/10.1038/s41420-026-03113-y","url":null,"abstract":"<p><p>Sepsis-associated acute kidney injury (S-AKI) is characterized by complex pathological mechanisms, primarily driven by oxidative stress and inflammation, with NADPH oxidase 4 (NOX4) playing a critical role. However, the regulatory mechanisms underlying NOX4 activation remain incompletely understood. In this study, we found that circulating levels of NOX4 and the chromatin acetylation \"reader\" bromodomain-containing protein 4 (BRD4) were significantly elevated in S-AKI patients and positively correlated with renal dysfunction markers. These clinical findings were further validated in both LPS-induced and cecal ligation and puncture (CLP)-induced S-AKI models, in which BRD4 and NOX4 were markedly upregulated in the kidney. Prominent induction was observed in renal tubular epithelial cells, and this upregulation was associated with exacerbated inflammation, oxidative stress, and renal injury. Pharmacological inhibition of NOX4 effectively mitigated these pathological changes in both models. Similarly, treatment with the BRD4 inhibitor JQ1 conferred renoprotection and downregulated NOX4. Mechanistically, chromatin immunoprecipitation assays demonstrated that upon LPS stimulation, BRD4 is recruited to the NOX4 promoter, facilitates the co-recruitment of the histone acetyltransferase P300, and promotes local histone H3 acetylation to directly activate NOX4 transcription. Importantly, NOX4 overexpression delivered by AAV, which was predominantly detected in renal tubules, largely abolished the protective effects of JQ1, indicating that NOX4 is a critical downstream target of BRD4. In conclusion, our findings identify the BRD4/P300/NOX4 transcriptional regulatory axis as a key pathogenic mechanism in S-AKI, offering a novel therapeutic insight for this condition.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A positive feedback loop between TKT and c-Myc drives TACE resistance in hepatocellular carcinoma.","authors":"Yifu Xiao, Mingyu Liu, Ying Zhou, Yunyuan Bao, Guoqing Zhang, Banglong Xu, Wenjie Zheng, Hui Zhao","doi":"10.1038/s41420-026-03125-8","DOIUrl":"https://doi.org/10.1038/s41420-026-03125-8","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) often receives transarterial chemoembolization (TACE), yet clinical benefit is limited by resistance driven by ischemia-induced adaptations. This study explains how transketolase (TKT) in the pentose phosphate pathway (PPP) modulates HCC progression and TACE refractoriness, and clarifies its mechanistic connection to oncogenic signaling. We integrated transcriptomic screening with analyses of TACE patient specimens, and performed gain and loss of function experiments across HCC cell lines. Functional assays, RNA-seq with pathway enrichment, western blotting, immunofluorescence, cycloheximide-chase and ubiquitination assays, and an orthotopic VX2 rabbit TACE model with imaging and immunohistochemistry were used. TKT emerged as a hub gene, was elevated in TACE-resistant patients, and promoted proliferation, migration, invasion, epithelial-mesenchymal transition, and apoptosis resistance. Mechanistically, TKT associates with RAF1, promoting phosphorylation of c-Raf at Ser338 and subsequent ERK activation, and stabilizes c-Myc by enhancing Ser62 phosphorylation and reducing ubiquitin-mediated degradation. Additionally, c-Myc enhances the transcriptional expression of TKT, creating a positive feedback loop between TKT and c-Myc. These findings identify a TKT/c-Myc positive feedback loop that underlies TACE resistance and HCC progression, nominating TKT as a biomarker of refractoriness and a therapeutic target to improve locoregional treatment outcomes.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc ions attenuates iridovirus infection through regulation of ferroptosis pathways.","authors":"Yanlin You, Mincong Liang, Xueqian Cao, Weiqiang Pan, Jian He, Kun Wu, Shaoping Weng, Jianguo He, Changjun Guo","doi":"10.1038/s41420-026-03114-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03114-x","url":null,"abstract":"<p><p>Zinc is widely acknowledged as an inducer of ferroptosis, a type of regulated cell death process. Generally, ferroptosis is known to facilitate viral replication. However, an intriguing aspect is that despite its role in inducing ferroptosis, zinc demonstrates broad-spectrum antiviral activity. This study focused on investigating how zinc ions inhibit the replication of the infectious spleen and kidney necrosis virus (ISKNV; an iridovirus) in mandarin fish (a teleost fish) through zinc influx-dependent ferroptosis activation. RNA-seq, enzyme activity assays, and transmission electron microscopy results revealed that zinc could promote ferroptosis in fish. Single-cell sequencing and in vivo validation confirmed that ISKNV infection triggered host ferroptosis, while pharmacological modulation showed that ferroptosis suppressed viral infection. Delving deeper into the mechanism, it was discovered that the expression of GPX4 and xCT partially reversed the antiviral effect of zinc, suggesting that the xCT/GPX4 axis mediated ferroptosis is a mechanistic participant. In vivo challenge assays further verified that zinc monotherapy reduced mortality by 25% and delayed disease progression, and these effects were abolished by co-treatment with the ferroptosis inhibitor vitamin C. This work sheds light on a zinc-ferroptosis axis as an unconventional antiviral defense, redefining both zinc's immune mechanism and the dual role of ferroptosis in viral infection.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMARCA4 activation engages FOSL1 to drive enhancer reprogramming and tumorigenic phenotypes in SMARCA4-deficient LUAD cells.","authors":"Hye-Ju Yang, Eun-Ju Kim, Sungho Kim, Sang-Hyun Song, Tae-You Kim","doi":"10.1038/s41420-026-03100-3","DOIUrl":"https://doi.org/10.1038/s41420-026-03100-3","url":null,"abstract":"<p><p>SMARCA4, the ATPase component of the SWI/SNF chromatin remodeling complex, is integral to the regulation of gene expression through modulation of chromatin accessibility. Although SMARCA4 is frequently inactivated in lung adenocarcinoma (LUAD), a subset of tumors exhibits elevated SMARCA4 expression, suggesting a context-dependent oncogenic function. However, the molecular mechanisms by which elevated SMARCA4 exerts oncogenic functions in LUAD remain unclear. Here, using a SMARCA4-deficient LUAD cellular model, we show that SMARCA4 overexpression reorganizes enhancer landscapes and establishes a cooperative transcriptional network involving FOSL1, thereby promoting cancer cell proliferation and tumorigenic phenotypes. Integrative multi-omics analyses revealed that SMARCA4 directly cooperates with FOSL1 at active enhancers, leading to the activation of tumor-associated transcriptional programs. Functionally, genetic depletion of FOSL1 or pharmacological inhibition of SMARCA4 reduced cell proliferation and migration and suppressed tumor growth in vitro and in vivo. Importantly, high co-expression of SMARCA4 and FOSL1 was associated with poor clinical outcomes in LUAD patient cohorts. Together, these findings define an epigenetic regulatory axis between SMARCA4 and FOSL1 induced by SMARCA4 activation in SMARCA4-deficient LUAD cells, thereby providing mechanistic insight into how SMARCA4 activates oncogenic regulatory programs in this specific cellular context.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"dMyc suppresses CTG-induced cytotoxicity in the Drosophila model of DM1 by reducing autophagy and cell death.","authors":"Dipti Chakraborty, Naorem Tarundas Singh, Shreya Borthakur, Mayanglambam Dhruba Singh","doi":"10.1038/s41420-026-03123-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03123-w","url":null,"abstract":"<p><p>Myotonic Dystrophy Type 1 (DM1) is a complex, genetic, and multisystemic disorder caused by the expansion of CTG trinucleotide repeats in the Dystrophia Myotonica Protein Kinase gene, leading to the formation of toxic RNA foci, which finally result in progressive muscle weakness, myotonia, and systemic complications affecting almost every organ system of the body. Despite its severity and high prevalence, effective therapeutic strategies remain elusive. Our study aims to identify a genetic modifier with therapeutic potential. We used transgenic flies expressing pathogenic CTG250 and CTG270 repeats as a Drosophila model of DM1, which recapitulated the hallmark features: formation of RNA foci, muscle fibre degeneration, impaired locomotor activity, and shortened lifespan. Drosophila Myc (dMyc), also known as diminutive, is a highly conserved transcription factor that plays a crucial role in cellular growth, metabolism, and autophagy. We found that targeted overexpression of dMyc significantly ameliorated disease phenotypes, including improved muscle integrity, enhanced motor function, extended lifespan, and reduced RNA foci. Our findings also revealed that dMyc expression is significantly reduced in flies with disease caused by abnormal CTG expansion. Overexpression of dMyc led to a marked decrease in autophagy and apoptosis. Our findings highlight impaired dMyc expression in CTG-mediated pathogenesis in the DM1 model and suggest that modulation of Myc expression could be a promising therapeutic intervention for DM1.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zona pellucida is required for oocyte actin cortex and oocyte-somatic cell interactions during oocyte growth.","authors":"Shoujing Liang, Weixi Xiang, Ruping Quan, Jiayu Su, Chao Lv, Hualin Huang, Hongmei Xiao","doi":"10.1038/s41420-026-03124-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03124-9","url":null,"abstract":"<p><p>Structural defects in the zona pellucida (ZP), caused by mutations in ZP genes, are a recognized cause of female infertility; however, their pathogenic mechanisms are not fully understood. Here, we investigated how two distinct ZP defects (complete absence and thinning) compromise fertility using Zp1^mut/mut and Zp2^mut/mut rat models. We found that ZP deficiency leads to stage-specific oocyte loss during early antral follicle development in vivo and arrests the maturation of fully grown oocytes in vitro, which also exhibit reduced diameter and mitochondrial dysfunction. From the secondary follicle stage onward, granulosa cells showed reduced proliferation, increased apoptosis, and impaired adhesion, culminating in a disorganized cumulus-oocyte complex morphology and disrupted steroidogenesis by the antral stage. Further analysis revealed that the specialized structures for oocyte-somatic cell interaction, namely transzonal projections and oocyte microvilli, were disorganized and reduced in number. This structural disruption was accompanied by a global perturbation of the bidirectional communication and physical adhesion network between the oocyte and its somatic niche, underscoring the ZP's essential role in organizing this functional microenvironment. At the molecular level, single-cell transcriptomic and protein analyses demonstrated that ZP deficiency induces a thinning of the oocyte cortical actin layer and dysregulation of cytoskeletal dynamics. This was associated with an upregulation of actin-regulating proteins, including TPM4 and ACTN1, and the engagement of focal adhesion-related pathways. The observed cortical actin disorganization provides a plausible mechanistic link to the concurrent abnormalities in microvilli and cell-cell adhesion. Collectively, our results establish the ZP as a critical structural scaffold that ensures oocyte cortical integrity and coordinates the surrounding somatic cell niche. Its disruption leads to a progressive failure in oocyte-somatic cell interaction and support, ultimately resulting in oocyte developmental impairment and loss. This study provides detailed mechanistic insights into the pathogenesis of ZP-related female infertility (particularly empty follicle syndrome).</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing of METTL16 protects granulosa cells from the cisplatin-induced ferroptosis in premature ovarian failure.","authors":"Jing Xiong, Ling He, Yongjing Zhang, Lifang Li","doi":"10.1038/s41420-026-03081-3","DOIUrl":"https://doi.org/10.1038/s41420-026-03081-3","url":null,"abstract":"<p><p>Premature ovarian failure (POF) and insufficiency induced by cisplatin are common complications associated with gynecological diseases. This study aims to investigate the role of N⁶-methyladenosine (m⁶A) methyltransferase METTL16 in cisplatin-induced ovarian granulosa cells ferroptosis. In cisplatin-treated ovarian tissue, the level of METTL16 was significantly elevated. Furthermore, METTL16 was also upregulated in cisplatin-stimulated granulosa cells. Functionally, silencing METTL16 inhibited iron accumulation and lipid peroxidation, while alleviating mitochondrial injury. Mechanistically, METTL16 was found to target NRF2, negatively regulating its RNA stability, and YTHDF2 facilitated the degradation of NRF2 mRNA. In summary, the METTL16/YTHDF2/NRF2 axis regulates ferroptosis in cisplatin-stimulated granulosa cells in POF. This study suggests that METTL16 may serve as a promising immunotherapeutic target for POF.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}