Cell Death & Disease最新文献

{"title":"Repeated ablations of mature Tmem10⁺ oligodendrocytes recapitulates key pathological features of multiple sclerosis with prolonged demyelination.","authors":"Feiyan Zhu, Haijiao Huang, Yuting Shu, Guoru Ren, Bo Jing, Honglin Tan, Wanxiang Jiang, Yiyuan Cui, Paul F Worley, Bo Xiao, Mina Chen","doi":"10.1038/s41419-025-07996-0","DOIUrl":"10.1038/s41419-025-07996-0","url":null,"abstract":"<p><p>Managing multiple sclerosis (MS), a chronic, neuroinflammatory and demyelinating disease, remains an unmet medical need. A great obstacle to developing therapeutic interventions altering the disease process is the lack of a suitable disease model recapitulating its core pathologies, especially the process of myelin damage and regeneration against the backdrop of persistent neuroinflammation. Now we report the generation and characterization of a new demyelination/remyelination model with key pathological features of MS through repeated ablations of Tmem10⁺ oligodendrocytes. Using the Tmem10-Cre driver that targets expression of diphtheria toxin receptor (DTR) in Tmem10⁺ (mature myelin-forming) oligodendrocytes, we conducted 3 rounds of Tmem10⁺ oligodendrocyte ablations over the span of 9 weeks in young adult mice by injecting diphtheria toxin (DT). Three rounds of the oligodendrocyte ablation caused prolonged demyelination and axonal injury in the backdrop of chronic neuroinflammation, including gliosis and lymphocyte infiltration. In response to the oligodendrocyte ablations, the proliferation and differentiation of OPCs were accelerated for the regeneration of myelin-forming oligodendrocytes, leading to spontaneous remyelination. This de-/re-myelination model presents a wide \"time window\" between the onset of demyelination and spontaneous remyelination, which makes it suitable for assessing the efficacy of therapeutic pro-remyelinating agents, as demonstrated by administering Benztropine to this demyelination model.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"691"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238187","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 CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.","authors":"Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna","doi":"10.1038/s41419-025-08030-z","DOIUrl":"10.1038/s41419-025-08030-z","url":null,"abstract":"<p><p>The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"693"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238084","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":"Hepatic steatosis and pyroptosis are induced by the hepatitis B virus X protein via B56α-METTL3 interaction-mediated m6A modification of the NLRP3 mRNA.","authors":"Ze-Bang Du, Tun Han, Yu-Xin Cai, Yu-Shi Shen, Jia-Shen Wu, Xiong Li, Hang-Tian Zhong, Bai-Heng Wu, Lei Zhang, Liang-Yu Wen, Xiao-Ming Luo, Zhong-Ning Lin, Yu-Chun Lin","doi":"10.1038/s41419-025-08019-8","DOIUrl":"10.1038/s41419-025-08019-8","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is one of the fastest-growing chronic liver diseases and is characterized by excessive steatosis, inflammation, and progressive liver injury. The hepatitis B virus (HBV) X protein (HBx) is a major viral factor that contributes to the onset and progression of MASH. Emerging evidence highlights the role of epigenetic modifications, particularly N6-methyladenosine (m6A), as prevalent modifications of mRNAs that play crucial roles in MASH pathogenesis by regulating mRNA stability, translation, processing, and nuclear export. However, the epigenetic mechanisms by which m6A modification contributes to HBx-related MASH remain poorly defined. In this study, we observed that NOD-like receptor protein 3 (NLRP3)-dependent pyroptosis and intracellular lipid accumulation are markedly elevated in the livers of HBx-transgenic (HBx-Tg) mice in vivo and in HBx-expressing hepatocytes in vitro, exacerbating liver injury and driving MASH progression. Integrated metabolomic and transcriptomic analyses of HBx-Tg mice revealed distinct gene expression alterations, suggesting a key role for m6A modification in mediating hepatic inflammation and lipotoxicity. Mechanistically, we identified methyltransferase-like 3 (METTL3) as a critical positive regulator of this process. HBx upregulated METTL3 expression and the m6A level of NLRP3 mRNA in HBx-expressing hepatocytes, whereas METTL3 knockdown or catalytic inactivation suppressed NLRP3-dependent pyroptosis. Further investigation revealed that METTL3 enhances NLRP3 mRNA stability via m6A modification at A2748 site in the coding sequence. Moreover, the protein phosphatase 2A (PP2A) B56α subunit was found to interact with the METTL3 methyltransferase domain (MTD), facilitating its enzymatic activity and further increasing NLRP3 m6A methylation, thereby promoting pyroptosis and lipid accumulation in HBx-expressing hepatocytes. Importantly, treatment with STM2457, a selective inhibitor targeting the METTL3 MTD, significantly attenuated hepatic inflammation, steatohepatitis, and lipotoxicity. Taken together, our findings advance the understanding of HBx-induced hepatic lipid accumulation, steatosis, inflammasome formation, and pyroptosis, and indicate that targeting METTL3 with STM2457 intervention is a promising approach for MASH treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"698"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238207","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":"ALIX mediates reversible gasdermin-D pore formation via the endosomal pathway to limit pyroptosis by active membrane repair.","authors":"Sylvia Otchere, Prafulla Shrestha, Himesh N Parmar, Jadyn F Perry, Brittany L Hofmeister, Michelle Steyn, Radhey S Kaushik, Adam D Hoppe, Natalie W Thiex, Ryan L Hanson, Jaime Lopez-Mosqueda, Gergely Imre","doi":"10.1038/s41419-025-07998-y","DOIUrl":"10.1038/s41419-025-07998-y","url":null,"abstract":"<p><p>Pyroptosis is a form of regulatory cell death characterized by membrane rupture and release of pro-inflammatory signals. In pyroptosis, Caspase-1 activation leads to the cleavage of gasdermin-D (GSDMD). Upon cleavage, GSDMD's N-terminal (N-GSDMD) fragments insert into the plasma membrane, oligomerize, and form pores. The molecular details that define whether GSDMD pore formation results in cell death or survival are largely unknown. In this study, we show that a shorter duration of membrane N-GSDMD pores (t ≤ 2 h), along with associated membrane permeability does not harm cellular viability. We demonstrate that N-GSDMD is removed, and membrane integrity is restored if the pyroptotic stimulus is washed out within 1 hour. In contrast, longer duration of N-GSDMD pore formation leads to large-scale membrane damage and cell death. Using a selective dynamin inhibitor and confocal microscopy, to co-label N-terminal GSDMD (N-GSDMD) and the early endosomal marker EEA1, we demonstrate that N-GSDMD is cleared from the plasma membrane via the endosomal pathway. Through stable ALIX knockdown and overexpression approaches, we further show that ALIX, a key accessory protein of the ESCRT machinery, regulates N-GSDMD pore dynamics by promoting its removal and facilitating membrane repair via N-GSDMD internalization. In summary, we show that the duration of N-GSDMD membrane pores is a decisive factor and ALIX-dependent mechanism facilitates N-GSDMD removal and restores membrane integrity. The identification of these factors can open the development of new therapeutic strategies in chronic inflammatory conditions by bolstering the cell's inherent self-healing potential.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"681"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238142","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":"PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.","authors":"Shiyi Yin, Yibo Zhai, Run Song, Jiannan Wu, Yongjiang Zhang, Miao Yu, Hongxia Ma, Mengmeng Shen, Xiaoyi Lai, Weina Jin, Yunqi Xu, Junqiang Yan","doi":"10.1038/s41419-025-08035-8","DOIUrl":"10.1038/s41419-025-08035-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP⁺/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 binding. Disrupting this interface abolished BCL-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD. Schematic summary. In normal neuronal cells, PARL can inhibit the release of apoptotic signals by interacting with Nur77. In the MPP⁺-induced PD model, PARL expression is reduced inhibits the apoptosis of dopaminergic neurons, and reduces cell viability. Mechanistic schema: Normal state: PARL-Nur77 complex stabilizes mitochondrial membrane integrity, inhibiting BCL-2 ubiquitination. MPP+ injury: PARL downregulation disrupts Nur77 binding, triggering BAX oligomerization and caspase-3 activation. Therapeutic rescue: Nur77 overexpression restores PARL-mediated anti-apoptotic signaling.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"700"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238131","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 cells in normal colon and colon cancers: importance of thyroid hormone signaling.","authors":"Mathieu Reslinger, Michelina Plateroti","doi":"10.1038/s41419-025-08005-0","DOIUrl":"10.1038/s41419-025-08005-0","url":null,"abstract":"<p><p>Thyroid hormones (THs, namely T3 and T4) regulate intestinal development and homeostasis via thyroid hormone nuclear receptors (TRs), which are T3-modulated transcription factors. Previous work has highlighted the importance of THs and the TRα1 receptor in intestinal stem cell biology and tumor formation, through actions on WNT, NOTCH, and BMP signaling pathways, which mediate epithelial-stromal cell interactions. Recent findings underscore the critical role of stromal cells in maintaining homeostasis and interacting with colonic stem cells. Stromal cells, especially cancer-associated fibroblasts (CAFs), are also essential in colorectal cancer (CRC). While the TH/TR signaling on gut epithelia-stromal interactions is well characterized in amphibians during the TH-dependent metamorphosis process, its function in the normal mammalian colon is still poorly defined, and in CRCs, it remains underexplored. In addition, it is worth underlining that TRα1 mutations in patients are responsible for Resistance to Thyroid Hormone-α (RTH-α) syndrome. This syndrome is a complex pathology that recapitulates typical traits of hypothyroidism, including gut malfunction. Up to now, very little is known about the cellular alterations in the gut of RTH-α patients. This review summarizes recent studies on the roles of T3 and TRα1 in colon physiopathology, with an emphasis on epithelial/stromal or tumor/stromal interactions via cell-cell signaling.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"699"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237862","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":"Zinc Finger Protein 82 regulates p53 protein stability through histone deacetylase and enhances neo-adjuvant chemotherapy in esophageal cancer.","authors":"Weiyan Peng, Hongpeng Wang, Xuejuan Sun, Zhong Xu, Lingxiang Zhang, Lin Ye","doi":"10.1038/s41419-025-07979-1","DOIUrl":"10.1038/s41419-025-07979-1","url":null,"abstract":"<p><p>Tumor suppressor genes silenced by CpG methylation uncover the molecular mechanism of tumorigenesis and potential tumor biomarkers. Our previous research found that the promoter of zinc-finger protein 82 (ZFP82) was highly methylated in multiple cancers, including esophageal cancer, which induces the occurrence and development of tumors. Here, we describe the frequent detection of methylation of the ZFP82 promoter CpG Island in patients who did not respond to neoadjuvant chemotherapy, indicating that ZFP82 may related to esophageal cancer chemo-resistance. We further verified that in esophageal cancer cells expressing wild-type p53, ZFP82 bound to the HDAC3 promoter and mediated its interaction with p53, leading to HDAC3 cleavage and reduction of p53 ubiquitin-dependent proteasomal degradation, thus enhancing wild-type p53 stability. In cells expressing mutant p53, ZFP82 interacted with HDAC3 to regulate the down-regulation of HSP 70, leading to degradation of mutant p53. Through both mechanisms, the restoration of ZFP82 enhanced the chemosensitivity in esophageal cancer cells expressing wild-type p53 or mutant p53, significantly inhibiting in vivo tumorigenicity of these cells. Analyses of the expression of ZFP82 and clinical data indicated that ZFP82 expression correlated with improved prognosis. Our results define a mechanism for p53 stabilization via ZFP82-dependent HDAC3 decay under genotoxic stress conditions and validate a candidate bio-marker of early prediction of patients who will respond to esophageal cancer neoadjuvant chemotherapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"694"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238110","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":"Adipocyte-specific Mlkl knockout mitigates obesity-induced metabolic dysfunction by enhancing mitochondrial functions.","authors":"Juliette Tokgozoglu, Valeria Pistorio, Mirko Minini, Pierre-Antoine Soret, Virginie Steunou, Jean-Louis Delaunay, Julien Castel, Serge Luquet, Ivan Nemazanyy, Carine Beaupère, Laetitia Dinard, Tatiana Ledent, Aurore L'honoré, Sara Lemoinne, Chantal Housset, Philippe Lesnik, Vlad Ratziu, Bruno Fève, Tounsia Aït-Slimane, Axelle Cadoret, Nicolas Chignard, Jérémie Gautheron","doi":"10.1038/s41419-025-08004-1","DOIUrl":"10.1038/s41419-025-08004-1","url":null,"abstract":"<p><p>Obesity is a global epidemic characterized by chronic low-grade inflammation and metabolic dysfunction, with adipose tissue playing a pivotal role in these processes. The mixed lineage kinase domain-like pseudokinase (MLKL) is a critical mediator of necroptosis but also exhibits noncanonical roles in metabolic regulation. This study aimed to investigate the adipocyte-specific functions of MLKL in obesity. Using adipocyte-specific Mlkl knockout (Mlkl^Adi-KO) mice, we observed reduced susceptibility to high-fat diet (HFD)-induced obesity, enhanced glucose tolerance, and improved insulin sensitivity. Mlkl^Adi-KO mice showed elevated energy expenditure independent of changes in food intake or locomotor activity, correlating with increased mitochondrial function and reduced lipid accumulation in white adipose tissue (WAT). Transcriptomic analyses of WAT revealed significant modulation of pathways linked to oxidative phosphorylation, inflammation, and lipid metabolism. Furthermore, metabolomic profiling highlighted reductions in TCA cycle intermediates, acylcarnitines, and pro-inflammatory amino acids in Mlkl^Adi-KO mice under HFD conditions. These findings were accompanied by improved hepatic lipid profiles and decreased steatosis, underscoring systemic benefits of adipocyte-specific Mlkl deletion. Mechanistically, Mlkl deficiency altered adipocyte differentiation. These results position MLKL as a promising therapeutic target for obesity and related metabolic disorders, emphasizing the need for future studies using conditional knockout and overexpression models to explore its cell-specific and noncanonical functions in metabolic regulation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"683"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238192","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":"Senescent macrophages in tumor: phenotypes, roles, and interventions.","authors":"Wenhui Shen, Yueyu Huang, Xuping Yang, Yutian Zhang, Yiyi Pan, You Xiao, Jiahui Wang, Changchun Wang, Weimin Mao, An Zhao","doi":"10.1038/s41419-025-08000-5","DOIUrl":"10.1038/s41419-025-08000-5","url":null,"abstract":"<p><p>The senescence of immune cells, including macrophages, that accompany the initiation and development of tumors has become a novel research hotspot. Recently, studies have reported the molecular characteristics of senescent macrophages (sMACs) in the tumor microenvironment (TME), including cell cycle arrest, senescence-associated secretory phenotype (SASP), and senescence-associated β-galactosidase phenotype (SA-β-gal), and these characteristics not only suggest that sMACs are functionally rich in the TME, but also have the potential to become biomarkers for the identification of sMACs. The in-depth study and analysis of sMACs dialogue and mediating the changes of signaling pathways related to tumor and immune cells will help us to better understand the balance between tumor and aging. Here, we review recent advances in sMACs, including phenotypical molecular characteristics, potential functions and intervention approaches.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"677"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237920","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 deubiquitinase USP9X and E3 ligase WWP1 orchestrate IGF2BP2 ubiquitination homeostasis to drive TNBC progression and cisplatin sensitivity.","authors":"Tian Xia, Jianyi Zhao, Zhengyu Zhang, Weilin Lu, Yuxin Wang, Xinrui Dong, Mingyi Sang, Linjie Ju, Xu Zhang, Jifu Wei, Qiang Ding","doi":"10.1038/s41419-025-08038-5","DOIUrl":"10.1038/s41419-025-08038-5","url":null,"abstract":"<p><p>The functional impact of post-translational modifications (PTMs) on many N6-methyladenosine (m6A) regulatory proteins remains unclear. Our previous study demonstrated that the m6A reader IGF2BP2 drives triple-negative breast cancer (TNBC) progression through epigenetic regulation. Here, we found that IGF2BP2 ubiquitination homeostasis was dynamically regulated by the opposing actions of USP9X (deubiquitinase) and WWP1 (E3 ligase). We further identified USP9X as a cisplatin-binding protein, whose inactivation upon cisplatin treatment shifts this balance toward WWP1-mediated IGF2BP2 degradation in TNBC. This suppressed IGF2BP2-mediated stabilization and translation of m6A-modified MYC/CDK6 mRNAs, thereby inhibiting TNBC progression. Notably, combined USP9X inhibitor WP1130 and low-dose cisplatin showed synergistic therapeutic efficacy against TNBC in both in vivo and in vitro models. Overall, our findings established that the USP9X/WWP1 axis maintained IGF2BP2 ubiquitination homeostasis to regulate m6A-dependent oncogenic functions in TNBC. Crucially, cisplatin uniquely disrupts this balance through USP9X binding, impairing IGF2BP2's m6A recognition capacity and revealing a novel UPS-mediated drug response mechanism specific to TNBC treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"703"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238053","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}