Cell Death & Disease最新文献

{"title":"The spliceosome component SNRPC promotes glioma progression by sustaining mitochondrial function and TNFAIP2 signaling.","authors":"Peng Ma, Jiang Wu, Zhen Ma, Kai Xu, Xingqi Wang, Kun Yuan, Ya Peng","doi":"10.1038/s41419-026-09065-6","DOIUrl":"10.1038/s41419-026-09065-6","url":null,"abstract":"<p><p>Human glioma is a devastating primary brain tumor with a dismal prognosis, necessitating the identification of novel therapeutic targets. The small nuclear ribonucleoprotein C (SNRPC), a core spliceosome component, is implicated in cancer, but its role in glioma remains unexplored. This study aimed to delineate the expression, function, and underlying mechanisms of SNRPC in human glioma. The bioinformatic analysis revealed that SNRPC is significantly upregulated in glioma tissues, with expression levels correlating strongly with higher tumor grade, aggressive molecular subtypes (IDH wild-type, 1p/19q non-codeleted), and poor patient prognosis, establishing it as a robust independent biomarker. Single-cell analysis pinpointed SNRPC enrichment in malignant glioma cells, and co-expression studies linked it to mitochondrial metabolism and oxidative phosphorylation. SNRPC expression is also upregulated in locally-resected glioma tissues and various glioma cell types. Functionally, silencing (by targeted shRNA) or knocking out (via CRISPR/Cas9 method) of SNRPC profoundly attenuated glioma cell proliferation, migration, and invasion, while inducing G1-S arrest and apoptosis. These effects were specifically observed in malignant glioma cells, sparing normal astrocytes. Mechanistically, loss of SNRPC led to severe mitochondrial dysfunction, characterized by impaired mitochondrial respiration, ATP depletion, membrane depolarization, and excessive ROS (reactive oxygen species) production. Conversely, SNRPC overexpression enhanced mitochondrial bioenergetics and promoted malignant phenotypes. SNRPC promoted glioma malignancy by regulating the expression of a key oncogene tumor necrosis factor alpha-induced protein 2 (TNFAIP2), which acts as a key downstream effector to drive increased cell proliferation and migration. Critically, SNRPC knockdown suppressed subcutaneous glioma xenograft growth and disrupted mitochondrial bioenergetics. Its knockout also impeded the intracranial glioma growth in an orthotopic mouse model. Our findings establish SNRPC as a pivotal driver of glioma malignancy by sustaining mitochondrial hyperfunction and TNFAIP2 expression essential for tumor cell proliferation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LARS regulates cellular senescence and autophagy in liver cancer cells.","authors":"Xiaodan Lin, Yanheng Chen, Caroline Hartmann, Lin-Feng Chen, Susan A Martinis","doi":"10.1038/s41419-026-09114-0","DOIUrl":"10.1038/s41419-026-09114-0","url":null,"abstract":"<p><p>Human cytoplasmic leucyl-tRNA synthetase (LARS) is known to catalyze the ligation of leucine to tRNA^Leu during protein biosynthesis. However, LARS also acts as a nutrient sensor in a non-canonical activity to regulate cell growth. In this investigation, LARS was determined to be expressed at high levels in human liver cancer, which correlated with poor clinical outcomes in patients. Knockdown of LARS in HepG2 liver cancer cells suppressed cell proliferation and growth, yet promoted cell migration, without affecting global protein translation. Using data from RNA sequencing, differentially expressed genes in response to LARS knockdown were significantly clustered in the cellular senescence pathway. Elevated p21 and p16 expression with increased senescence-associated β-galactosidase activity was observed in LARS knockdown HepG2 cells. In addition, autophagy with increasing autophagic flux was triggered in LARS knockdown HepG2 cells. Furthermore, the depletion of LARS induced oxidative stress with increased production of reactive oxygen species and decreased mitochondrial membrane potential. Importantly, re-expression of shRNA-resistant LARS largely rescued the senescence, autophagy, and oxidative stress caused by LARS knockdown, confirming the specificity of these effects. These findings suggest that LARS plays a role in regulating liver cancer cell proliferation via multiple cellular responses and may serve as a promising therapeutic target in liver cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From neural loss to regeneration: modulating cell death to enhance pluripotent stem cell graft survival and integration.","authors":"Ouye Chen, Kelvin K Hui, Fabian Raudzus, Jeffrey T Henderson","doi":"10.1038/s41419-026-09066-5","DOIUrl":"10.1038/s41419-026-09066-5","url":null,"abstract":"<p><p>Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted cells. These challenges currently limit the reproducibility and clinical translation of PSC-based therapies. Here, we examine these barriers with a particular focus on ischemic stroke and Parkinson's disease, two conditions that represent complementary models of acute and chronic neuronal loss and are among the most advanced indications for PSC-based transplantation. We discuss how programmed cell death signaling contributes not only to neuronal loss in these disorders but also to the limited survival of transplanted PSC-derived grafts. Building on this mechanistic framework, we highlight strategies that may improve graft survival and functional integration. Specifically, we propose an integrated approach that combines modulation of programmed cell death pathways, targeted activation of RAS signaling, optimization of mitochondrial health, and use of biocompatible scaffolds to support neuronal maturation and network integration. Together, these strategies provide a conceptual framework for improving the reliability and therapeutic efficacy of PSC-based cell transplantation therapies and accelerating their translation toward clinical application. Overview of strategies to enhance PSC-derived neural graft survival and integration through modulation of cell death pathways, RAS signaling, mitochondrial function, and extracellular scaffolds. Created in BioRender. Raudzus, F. (2026) https://BioRender.com/blr0ycj .</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming IGF1R-mediated resistance to oncolytic HSV1 and radiotherapy via triple combination therapy.","authors":"Alexandra A Miller, Min-Hye Noh, Jin Muk Kang, Jiyeon Kim, Lily Nguyen, Amanda S Kouaho, Grace Nguyen, Minxin Huang, Stephanie M Bean, Joshua Davis, Matthew P Mullarkey, Sunil Krishnan, Zhongming Zhao, E Antonio Chiocca, Tae Jin Lee, Ji Young Yoo","doi":"10.1038/s41419-026-09090-5","DOIUrl":"10.1038/s41419-026-09090-5","url":null,"abstract":"<p><p>FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced Insulin-like growth factor 1 receptor (IGF1R) signaling drives feedback pro-survival and proliferative pathways in tumor cells and evaluated the therapeutic potential of combining IGF1R blockade with oHSV and RTx. We first demonstrated that oHSV activates IGF1R signaling in vitro and in vivo, promoting tumor proliferation. While IGF1R-targeted monotherapies have shown limited cytotoxicity, its combination with oHSV led to a modest but significant increase in cytotoxicity across tested breast cancer (BC) and primary glioblastoma (GBM) cells in vitro and in vivo xenograft models. Furthermore, we observed that co-treatment with oHSV and RTx robustly activated both IGF1R and YAP1 in resistant cells, revealing the IGF1R/YAP1 axis as a key mediator of resistance to dual oHSV and RTx therapy. Notably, the triple combination of oHSV, RTx, and IGF1R blockade yielded synergistic anti-tumor effects, abolished YAP1 expression and nuclear localization, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings identify the IGF1R/YAP1 axis as a critical driver of resistance to oHSV and RTx and provide a strong rationale for the clinical evaluation of this triple-combination strategy to enhance therapeutic efficacy in patients with BC and GBM.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAP2K6 reprograms NAD⁺ metabolism via the HMGA1-NAMPT axis to sensitize ovarian cancer cells to PARP inhibition.","authors":"Ming Wen, Zhuohang Chen, Dongdong Zhan, Mingwei Liu, Shuran Tan, Fang Zhu, Siyu Yang, Jinru Xie, Yu Zhang, Jianjian Li, Lunquan Sun, Rong Tan","doi":"10.1038/s41419-026-09104-2","DOIUrl":"10.1038/s41419-026-09104-2","url":null,"abstract":"<p><p>PARP inhibitors (PARPi) selectively target cancers with homologous recombination deficiency (HRD), yet emerging evidence suggests that additional determinants beyond BRCA/HRD status modulate PARPi response. Here, by integrating unbiased proteomic profiling with systematic drug-response phenotyping across 11 ovarian cancer cell lines, we identify MAP2K6 as a previously unrecognized regulator of PARP1 activation and an important determinant of PARP inhibitor sensitivity in BRCA-wild-type ovarian cancer. MAP2K6 promotes global PARP1-mediated PARylation and enhances cellular responsiveness to the PARP inhibitor olaparib both in vitro and in vivo. Mechanistically, MAP2K6 can phosphorylate and activate HMGA1, which in turn transcriptionally upregulates NAMPT, resulting in increased intracellular NAD⁺ levels, and sustained PARP1 activation. Genetic depletion of HMGA1 or NAMPT abolishes MAP2K6-driven PARylation and PARPi sensitization, whereas loss of MAP2K6 reduces NAD⁺ levels, attenuates PARP1 activation, and confers resistance to PARPi. We propose that MAP2K6 promotes PARP inhibitor sensitivity by coupling metabolic control of NAD⁺ supply to PARP1 activation, thereby potentially helping extend the therapeutic scope of PARP inhibition beyond homologous recombination-deficient ovarian cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stromal BMP signalling maintains stem cell genome integrity and prevents gastric cancer initiation.","authors":"Zihao Li, Zhengting Wang, Ruichen Yang, Jiarui Zhao, Shaoyang Zhang, Liuchun Feng, Haiyu Shen, Hua Yue, Zhenlin Zhang, Xiaolin Guo, Dengli Hong, Yuji Mishina, Ye-Guang Chen, Qiang Wu, Huijuan Liu, Baojie Li","doi":"10.1038/s41419-026-09088-z","DOIUrl":"10.1038/s41419-026-09088-z","url":null,"abstract":"<p><p>Gastric cancer primarily originates from gastric stem/progenitor cells and is driven by somatic mutations. Although Helicobacter pylori is the main risk factor, how it drives malignancy is still not well understood. Analysis of single-cell RNA sequencing data reveals that human gastric cancer correlates with suppressed BMP signalling, a crucial niche signal for gastric stem cells, in stromal cells rather than epithelial cells. Genetic disruption of BMP signalling in Col1a2⁺ stromal cells or Acta2⁺ myocytes/pericytes alone, but not in gastric stem cells themselves, triggers mutations in gastric stem cells and initiates cancer development. Mechanistically, loss of BMP signalling increases stromal production of Wnt ligands, which dose-dependently drive transcription-replication collisions, R-loops, and DNA damage in gastric stem cells. The resulting DNA damage and carcinogenesis can be prevented by small-molecule inhibitors targeting Wnt pathway. Importantly, we identify inflammation as a key disruptor of stromal BMP signalling, as seen in patient samples with chronic atrophic gastritis and H. pylori-infected mouse gastric samples, which is associated with DNA damage. Together, these findings show how chronic inflammation derails niche signalling to drive stem cell mutations and gastric cancer and highlight promising avenues for early prevention.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-faced metabolic reprogramming powers proliferation: FGF21 drives lung squamous carcinoma progression via CaMKII-DRP1-mediated mitochondrial fission.","authors":"Xiao-Xin Pu, Yan Zhang, Bao-Yi Liu, Xiao-Jie Song, Yu-Wen Xue","doi":"10.1038/s41419-026-09084-3","DOIUrl":"10.1038/s41419-026-09084-3","url":null,"abstract":"<p><p>Fibroblast growth factor 21 (FGF21) is upregulated in lung squamous cell carcinoma (LUSC) tissues, cell lines, and tumor-conditioned media. Functional studies using LUSC cell lines (H1703, H520) demonstrate that FGF21 promotes cancer cell proliferation, migration, invasion, and tumor sphere formation in vitro. This pro-tumorigenic effect was validated in vivo through xenograft models, where intra-tumoral FGF21 administration accelerated tumor growth. Mechanistically, FGF21 activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates dynamin-related protein 1 (DRP1, encoded by DNM1L) at Ser616. Phosphorylated DRP1 translocates to mitochondria, inducing mitochondrial fission. Metabolic analyses revealed that FGF21 remodels cellular energetics in a cell type-specific manner, enhancing glycolysis in H520 cells and oxidative phosphorylation (OXPHOS) in H1703 cells, consistent with their inherent predominant metabolic states. Knockdown of DRP1 or pharmacological inhibition of CaMKII (KN93) abolished FGF21-driven mitochondrial fission, metabolic reprogramming, and tumor-promoting effects. Collectively, FGF21 acts as a tumor-promoting factor in LUSC by activating the CaMKII/DRP1-Ser616 axis to induce pathological mitochondrial fission and metabolic reprogramming, identifying this pathway as a potential therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircBRWD3 promotes non-small cell lung cancer progression through enhancing the stability of TRIM25 to increase p53 ubiquitin degradation and upregulating SPTBN2.","authors":"Yanhua Zhu, Yuefeng He, Mei Xiao, Lei Guo, Xiao Liu, Xi Chen, Jiezhen Liu, Xu Chen, Yanliang Zhang","doi":"10.1038/s41419-026-09103-3","DOIUrl":"10.1038/s41419-026-09103-3","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) play crucial roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. In this study, we found a novel circRNA, hsa_circ_0001936(circBRWD3), in NSCLC and investigated the biological role of circBRWD3 in NSCLC progression in vitro and in vivo. qRT-PCR was used to quantify the expression of circBRWD3 in NSCLC tissues, serum and cells. Cell growth curves, colony formation, Edu assay and transwell assays were conducted to study the function of circBRWD3. Finally, the molecular mechanism of circBRWD3 was revealed by Bioinformatic analyses, RNA pull-down analysis, RNA Fluorescence in situ hybridization (FISH), RNA-Binding Protein Immunoprecipitation (RIP), western blot, dual-luciferase reporter gene assays and rescue experiments. Our results showed that circBRWD3 was upregulated in NSCLC tumor tissues, patient serum and cell lines. CircBRWD3 knockdown inhibited NSCLC cells' growth and metastasis both in vitro and in vivo, while circBRWD3 overexpression had the opposite effect. Mechanistically, circBRWD3 binds to the TRIM25 protein to enhance its stability and mediate ubiquitin degradation of the p53 protein. In addition, circBRWD3 acted as a sponge for miR-135a-5p and miR-135b-5p to regulate the expression of SPTBN2, which promoted NSCLC progression. Our findings uncovered a tumor oncogenic function of circBRWD3 in NSCLC through the regulation of TRIM25 protein stability and miR-135a-5p/miR-135b-5p/SPTBN2 axis. CircBRWD3 may act as a promising oncogenic biomarker and therapeutic target for NSCLC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 PLAU-ITGB1-TGF-β axis orchestrates spatiotemporal reprogramming of fibroblasts at the invasive front to drive dual immunosuppressive niche and immunotherapy resistance in oral squamous cell carcinoma.","authors":"Yili Xiong, Shaopeng Liu, Lianyu Zhao, Xinze Liu, Hanzhi Zhang, Haoran Wang, Dongsheng Zhang, Changlong Wang, Haiwei Wu","doi":"10.1038/s41419-026-09110-4","DOIUrl":"10.1038/s41419-026-09110-4","url":null,"abstract":"<p><p>The initiation and progression of cancer are driven by the dynamic interplay between somatic mutations and the tumor microenvironment. Identifying core cell populations driving malignant transformation and understanding the intercellular interactions within the tumor microenvironment are, therefore, crucial for early diagnosis and effective treatment. Here, we construct a spatiotemporal atlas of oral squamous cell carcinoma (OSCC) progression by integrating multi-omics approaches. Our analysis reveals that the critical driver gene PLAU activates the TGF-β pathway via ITGB1, thereby promoting the conversion of fibroblasts into the COL11A1⁺ fibroblast (COL11A1⁺ Fib). These specialized fibroblasts remodel the extracellular matrix (ECM), collectively establishing an immunosuppressive niche composed of malignant epithelial cells, COL11A1⁺ Fib, and regulatory T cells (Tregs). Importantly, targeting COL11A1⁺ Fib alleviates this immunosuppressive niche and curbs OSCC progression. Our findings underscore the potential of COL11A1⁺ Fib as a predictive biomarker, especially in combination with immunotherapy. Collectively, this work demonstrates that the PLAU-ITGB1-TGF-β axis drives the formation of an Epi-COL11A1⁺ Fib-Treg immunosuppressive niche that fuels OSCC malignancy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SUV39H2-mediated NCOA4 methylation controls ferritinophagy and ferroptosis in triple-negative breast cancer.","authors":"Lingxia Liu, Xinyun Pei, Ding Li, Ying Huo, Zhaoting Wang, Qiu Zhang, Yuan Yue, Bao Deng, Minmin Yu, Tong Xu, Lei Zhong, Xianhui Ruan, Xichuan Li","doi":"10.1038/s41419-026-09008-1","DOIUrl":"10.1038/s41419-026-09008-1","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) exhibits iron homeostasis that supports tumor growth and proliferation, yet the regulatory mechanisms controlling iron flux remain poorly defined. Here, we identify a ferritinophagic cargo receptor NCOA4 as a novel substrate of the lysine methyltransferase SUV39H2, uncovering a previously unrecognized mechanism that regulates ferritinophagy and ferroptosis. SUV39H2 directly binds and mono-methylates NCOA4 at lysine 356, a modification that reduces NCOA4 stability. Mechanistically, K356 methylation enhances NCOA4 interaction with the E3 ligase HERC2, promoting its ubiquitination and proteasomal degradation. This degradation increases FTH1 stability, suppresses ferritinophagic flux, limits iron release, maintains the high-risk iron homeostasis and ferroptosis resistance, ultimately promoting tumor proliferation and chemoresistance. Conversely, genetic or pharmacologic inhibition of SUV39H2 (OTS186935) inhibit NCOA4 methylation, stabilizes NCOA4 protein, enhances ferritinophagy, and triggers ferroptosis. Furthermore, SUV39H2 inhibition sensitizes TNBC cells to chemotherapy in vitro and in vivo, indicating OTS186935 treatment is a feasible therapeutic strategy. Collectively, the SUV39H2-NCOA4-HERC2 axis as a critical regulatory pathway in iron metabolism and ferroptosis, and highlight inhibition of NCOA4 K356 methylation as a promising therapeutic target in TNBC. The mechanistic scheme of SUV39H2 depletion to facilitate ferroptosis in TNBC. A SUV39H2 binds and methylates NCOA4, which enhanced the interaction between NCOA4 and the E3 ubiquitin ligase HERC2, leading to NCOA4 ubiquitination and proteasomal degradation. As a result, iron metabolism was reprogramed via enhancing ferritinophagy, leading to an increase in the level of iron, ultimately triggering ferroptosis. B Cell-state transitions induced by SUV39H2.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}