Cell Death Discovery最新文献

{"title":"Exon junction complex and nuclear pore complex components preferentially govern the nuclear export of spliced lncRNAs.","authors":"Sondas Saeed, Weijie Wang, Chaoqun Chen, Xiaokun Yuan, Siqi Zhao, Xin Xu, Xinyi Xu, Jiaxin Liu, Shuai Hou, Jinsong Yan, Haixin Lei","doi":"10.1038/s41420-026-03246-0","DOIUrl":"10.1038/s41420-026-03246-0","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) are crucial regulators of gene expression, but how spliced lncRNAs destined for the cytoplasm are exported from the nucleus remains unclear. Using LINC00998 and ANCR as cytoplasmic lncRNA reporters, in vivo-assembled lncRNPs were purified via MS2-MBP-based affinity purification, and proteins in the lncRNPs were identified by mass spectrometry. An siRNA screen followed by RNA FISH showed that while knockdown of the TREX-TAP pathway components UAP56 and TAP blocked the export of both lncRNAs and mRNAs, depletion of ALYREF, the exon junction complex (EJC) core protein eIF4A3, or the nuclear pore complex (NPC) component NUP98 preferentially impaired lncRNA export without significantly affecting spliced mRNAs. This lncRNA-biased retention phenotype was also observed upon depletion of other EJC components, Y14 or MAGOH/MAGOHB, and at least 9 additional NPC components. In contrast, depletion of NUP160 or NUP205 caused strong retention of spliced lncRNAs and partial retention of spliced mRNAs. Consistent with these findings, stable knockdown of eIF4A3 and NUP98 predominantly increased nuclear accumulation of endogenous lncRNAs, whereas NUP160 depletion affected both RNA classes. Overall, our results demonstrate that although spliced lncRNAs utilize the canonical mRNA export machinery, they exhibit a distinct and preferential dependency on specific EJC and NPC components.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410544","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":"FOXM1 inhibition primes terminal differentiation of human iPSC-derived hepatocytes.","authors":"Kayque Alves Telles-Silva, Lara Pacheco, Sabrina Komatsu, Fernanda Chianca, Gustavo Chagas, Gabrielly Cristine Martins, Maria Gridina, Daria Panchenko, Valdemir Melechco Carvalho, Elia G Caldini, Veniamin S Fishman, Michelle Arkin, Ernesto Goulart, Mayana Zatz","doi":"10.1038/s41420-026-03178-9","DOIUrl":"10.1038/s41420-026-03178-9","url":null,"abstract":"<p><p>Human iPSC-derived hepatocytes are widely used in disease modeling. However, late embryonic development in the human liver remains elusive, which hinders differentiation. During late liver embryonic development, Topoisomerase II (TOP2) is downregulated; however, its role in differentiation is unclear. We replicated the TOP2 silencing at birth and identified a transcription factor crucial for hepatocyte differentiation in vitro. Subtoxic inhibition of TOP2 reduces nuclear chromatin condensation without causing DNA damage. RNA-seq analysis revealed that TOP2 inhibition induced cell cycle arrest, accompanied by FOXM1 downregulation. ATAC-seq confirmed that TOP2A inhibition decreased chromatin accessibility and modulated the Wnt/β-catenin pathway. Proteomic analysis demonstrated that FOXM1 inhibition mimicked TOP2A-mediated cell cycle arrest and reduced the levels of fetal hepatocyte proteins. Prolonged FOXM1 inhibition results in increased hepatocyte polyploidization, enhanced CYP450 activity, and improved lipid metabolism. Our findings suggest that FOXM1 inhibition promotes terminal differentiation of human iPSC-derived hepatocytes, potentially paving the way for understanding late embryonic development in the human liver.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410588","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":"BET inhibition unmasks a targetable glycolytic dependency through a HIF1α stabilization and driven transcriptional program in a defined subset of triple-negative breast Cancer.","authors":"Teresa Rossi, Egidio Iorio, Mattea Chirico, Maria Elena Pisanu, Federica Torricelli, Alessia Ciarrocchi, Mariaelena Pistoni","doi":"10.1038/s41420-026-03230-8","DOIUrl":"10.1038/s41420-026-03230-8","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterized by transcriptional and metabolic heterogeneity, which influences its response to therapeutics. Epigenetic drugs such as Bromodomain and Extra-Terminal domain inhibitors (BETi) are no exception to this variable response. However, the determinants of BETi sensitivity and the underlying mechanisms of response remain poorly understood, particularly in the context of metabolic reprogramming. Here, we investigated the responses to the BETi JQ1 and OTX015 across a heterogeneous panel of TNBC models. We found that the susceptibility to BETi partially correlates with basal BRD4 protein levels, but only in contexts characterized by high baseline cMYC levels, where BETi treatment triggers an upregulation of glycolytic genes, an effect that is absent in models displaying an intrinsically glycolytic phenotype. While the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) is effective as a single agent in the glycolytic-prone setting, it has limited efficacy in other TNBC models. Strikingly, a notable additive effect is visible when BETi are combined with 2-DG, leading to significant apoptotic induction, specifically in the BETi-responsive cells, whereas this additive effect is not observed in the glycolysis-driven models. Mechanistically, we identified that BETi induces the HIF1α transcriptional program in cMYC-high cells, which upregulates key glycolytic enzymes. HIF1α depletion reduced this response, confirming that HIF1α is functionally required for this adaptive rewiring. In conclusion, TNBC cells adapt to BETi by undergoing HIF1α-mediated metabolic rewiring towards glycolysis. This adaptive response creates a vulnerability, rendering these tumors sensitive to the combination of BET and glycolysis inhibitors. By mapping a transcriptional-metabolic axis that dictates BETi sensitivity, this study moves beyond the identification of a resistant subset of TNBC to reveal a deeper principle: targeted inhibition can actively reprogram cellular circuitry, thereby constructing its own unique therapeutic vulnerability. Thus, the path to overcoming resistance may lie not in evading this rewiring, but in strategically exploiting the alternative dependencies it creates.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410618","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 emerging Nexus of STING signaling and ferroptosis: from mechanisms to therapeutic opportunities.","authors":"Xixi Lin, Yihong Wen, Jiaheng Lang, Ziyu Zhu, Zijie Guo, Linbo Wang, Feiyang Ji, Lili Zhi, Jichun Zhou","doi":"10.1038/s41420-026-03214-8","DOIUrl":"10.1038/s41420-026-03214-8","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a cornerstone of innate immunity, and ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, have traditionally been studied as distinct entities. However, emerging evidence reveals a complex and bidirectional crosstalk between these two pathways with profound implications for disease pathogenesis and therapy. This review systematically synthesizes the current understanding of the multifaceted interactions between the cGAS-STING pathway and ferroptosis. We detail the mechanisms by which STING signaling promotes ferroptosis through iron metabolism (e.g., NCOA4-mediated ferritinophagy), lipid peroxidation (e.g., via ACSL4 interaction), and GPX4 autophagic degradation. Conversely, we explore how ferroptosis, through mitochondrial DNA release and lipid peroxidation products, can activate the cGAS-STING pathway, amplifying immune and inflammatory responses. A novel, non-canonical role for mitochondrially-localized cGAS in suppressing ferroptosis independent of STING is also highlighted, adding a layer of complexity to this interplay. We consolidate evidence of this crosstalk across a spectrum of diseases, including cancer, infectious diseases, neurodegenerative disorders, and ischemia-reperfusion injuries. In cancer, leveraging this interplay-particularly by inducing ferroptosis to activate STING-dependent anti-tumor immunity-presents promising therapeutic strategies. In contrast, for inflammatory and organ injuries, concurrent inhibition of both pathways may mitigate damage. This review underscores the STING-ferroptosis axis as a critical regulatory node and a promising frontier for developing novel therapeutic interventions across diverse human diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396138","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":"Spontaneous aging of mature amyloids alters structural stability, cytotoxicity, and susceptibility to biological clearance.","authors":"Maksim I Sulatsky, Olga V Stepanenko, Arina A Kayda, Olesya V Stepanenko, Ekaterina V Mikhailova, Anna I Sulatskaya","doi":"10.1038/s41420-026-03245-1","DOIUrl":"10.1038/s41420-026-03245-1","url":null,"abstract":"<p><p>Accumulation of amyloid fibrils is a key factor in the pathogenesis of progressive diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, as well as systemic amyloidosis. Although amyloid deposits are known to persist in vivo for years or even decades, it remains unclear how the structure and biological properties of mature fibrils evolve during prolonged post-assembly residence. Here, we addressed this question using a simplified cell-free aqueous model designed to isolate the intrinsic time-dependent behavior of mature amyloid aggregates from the complexity of the biological milieu. Specifically, we investigated the long-term evolution of two polymorphs of lysozyme amyloid fibrils as model systems with distinct clustering propensities that mimic the diversity of amyloid deposits. We challenge the assumption of amyloid stability by demonstrating their spontaneous degradation over 16 months at physiological temperature, a process we define as amyloid \"aging\". This process is characterized by aggregate declustering, fibril shortening, and progressive depolymerization into monomeric subunits, accompanied by a pronounced reduction in intrinsic toxicity across multiple human cell lines. Notably, \"aged\" fibrils were disassembled and degraded more efficiently than freshly prepared aggregates by the molecular chaperone α-B-crystallin and immune-associated proteases, including matrix metalloproteinase-9 and cathepsins B and D. However, this enhanced degradation revealed a paradox: accelerated processing of \"aged\" amyloids did not always reduce cytotoxicity and, in some cases, even exacerbated it, consistent with the generation of biologically active fibril-derived species rather than their complete conversion into non-toxic monomers. We provide the first systematic evidence that mature amyloids are dynamic structures undergoing spontaneous degradation that fundamentally alters their cytotoxicity and susceptibility to biological clearance. Our results introduce amyloid aging as a previously underappreciated dimension of amyloid biology and emphasize the need to account for fibril \"age\" when evaluating pathogenic potential and developing anti-amyloid therapeutic strategies. Spontaneous \"aging\" of amyloid fibrils leads to suprastructural remodeling: declustering, fibril shortening, and attenuated cytotoxicity. While \"aged\" aggregates are degraded more efficiently by immune-associated proteases and α-B-crystallin than \"fresh\" fibrils, this enhanced degradation does not reduce cytotoxicity and, in some cases, exacerbates it, highlighting the complex interplay between aggregate maturity and biological outcomes.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403691","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 a non-canonical TREM2-S100A9 axis that drives pro-tumorigenic macrophage polarization and sensitizes ovarian clear cell carcinoma to IL-17 blockade.","authors":"Shi Ti Zhang, Shi-Mei Zhang, Fan Jiang, Hua-Ju Huang, Meng-Nan Long, Hao Ai, Li Hong Liu","doi":"10.1038/s41420-026-03244-2","DOIUrl":"10.1038/s41420-026-03244-2","url":null,"abstract":"<p><p>The aggressive progression and significant chemotherapy resistance of ovarian clear cell carcinoma (OCCC) are closely related to the immunosuppressive tumour microenvironment (TME), but its potential molecular drivers are still unclear. The core of this process is the M2 polarisation of tumour-associated macrophages (TAMs), which regulates the tumour-promoting microenvironment. This study reveals a new and key signal axis responsible for this pathological intercellular dialogue. We confirmed that TREM2 is highly expressed on OCCC-related TAMs and plays a key role in its M2 differentiation. In terms of mechanism, we found that TREM2 bypassed its classic signal adaptor and directly interacted with the calcium-binding protein S100A9. This unprecedented interaction acts as a molecular switch, specifically activating the IL-17 signalling pathway. As a result, the TREM2-S100A9-IL-17 cascade reaction strongly drives M2 polarisation, which in turn promotes the proliferation, migration and invasion of OCCC cells. The key is to inhibit IL-17A by gene silencing S100A9 or using the pharmacology of clinical-grade antibody secukinumab. These tumour-promoting effects are completely eliminated in both in vitro and preclinical xenotransplantation models. This study reveals a new mechanism by which macrophages drive cancer progression, and determines that the TREM2-S100A9-IL-17 axis is a key molecular weakness, which provides a strong basis for the reuse of anti-IL-17 therapy to disintegrate the OCCC immunosuppression barrier.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403679","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":"Upregulation of macrophage UPP1 promotes lung adenocarcinoma metastasis through an mtROS-cGAS-NLRP3 inflammasome axis.","authors":"MingTao Feng, Chao Gao, YueChao Yang, Deheng Li, Changshuai Zhou, Lei Chen, Yongxiang Su, Yiqun Cao, Liangdong Li, Yang Gao","doi":"10.1038/s41420-026-03226-4","DOIUrl":"10.1038/s41420-026-03226-4","url":null,"abstract":"<p><p>Metastasis and immunosuppression remain major barriers to effective treatment of lung adenocarcinoma (LUAD), yet the metabolic mechanisms governing the pro-tumor functions of tumor-associated macrophages are incompletely understood. In this study, we identified Uridine Phosphorylase 1 (UPP1) as a macrophage-enriched metabolic regulator associated with LUAD progression. By integrating single-cell RNA sequencing with clinical cohort analyses, we found that UPP1 was preferentially expressed in tumor-associated macrophages and was associated with adverse clinical outcomes. Functional and mechanistic studies demonstrated that dysregulated UPP1 disrupted nucleotide homeostasis, leading to mitochondrial reactive oxygen species accumulation and mitochondrial DNA leakage. These mitochondrial stress signals activated the cGAS-STING pathway, which preferentially engaged NLRP3 inflammasome signaling rather than canonical antiviral responses. Consequently, macrophages underwent pyroptosis and released elevated levels of interleukin-1β (IL-1β). Through paracrine signaling, macrophage-derived IL-1β promoted epithelial-mesenchymal transition in LUAD cells and enhanced their invasive capacity in vitro. Consistent with these findings, co-injection of UPP1-overexpressing macrophages significantly increased spontaneous lung metastasis in vivo. Clinically, elevated UPP1 expression served as an independent predictor of poor survival. Furthermore, pharmacological blockade of this signaling cascade or neutralization of IL-1β attenuated macrophage-induced malignant phenotypes in tumor cells, highlighting the therapeutic relevance of this pathway. Collectively, our findings identify a macrophage-specific immunometabolic circuit in which UPP1-driven mitochondrial stress activates the mtROS-cGAS-NLRP3 axis, promoting IL-1β-dependent macrophage-tumor crosstalk and metastatic progression. These results suggest that UPP1 may serve as both a prognostic biomarker and a potential therapeutic target in LUAD.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396175","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":"Regulation of acute myocardial infarction by CircTMCC1 through mitochondrial dysfunction and AMPK/mTOR-driven M1 macrophage polarization: role in QFR assessment.","authors":"Mengmeng Ren, Shu He, Mengyang Duan, Boyu Chi, Zhiyuan Chen, Zhenyu Zhao, Zhongga Ciren, Yangzong Qiangba, Yahong Fu, Gaochao Wang, Liang Yuan, Fenghui An, Enzhi Jia","doi":"10.1038/s41420-026-03213-9","DOIUrl":"10.1038/s41420-026-03213-9","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) have been implicated in various cardiovascular diseases and hold promise as diagnostic biomarkers and therapeutic targets. However, the roles and mechanisms of circRNAs in coronary artery disease (CAD) and its severe complication, acute myocardial infarction (AMI), remain unclear. CircRNA sequencing, fluorescence in situ hybridization, and quantitative PCR were used to assess circTMCC1 expression in human coronary artery segments, peripheral blood mononuclear cells (PBMCs) from CAD patients, M1 macrophages, and an AMI mouse model. Multiple analytical methods were employed to investigate the predictive value of circTMCC1 for quantitative flow ratio (QFR) measurements. In vitro, we employed plasmid overexpression, small interfering RNA transfection, flow cytometry, immunofluorescence, reactive oxygen species (ROS), and mitochondrial membrane potential assays. In vivo, Masson's trichrome, hematoxylin and eosin staining, and immunohistochemistry were performed. Mechanistic investigations included bioinformatics, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, western blotting, and immunofluorescence. CircTMCC1 was significantly upregulated in CAD patients (p < 0.001) and associated with poor prognosis in AMI mouse models. CircTMCC1 was highly expressed in M1 macrophages (p < 0.001), and silencing its expression reduced M1 polarization, improved cardiac function after infarction, and regulated mitochondrial autophagy. Mechanistically, circTMCC1 facilitates the interaction between annexin A1 and the E3 ligase TRIM38, leading to annexin A1 degradation. Additionally, the AMPK/mTOR signaling pathway was identified as a downstream target of circTMCC1. These findings suggest that circTMCC1 may serve as a promising diagnostic biomarker and therapeutic target for CAD and AMI, potentially improving prognosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396157","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":"Multi-metal cooperation drives chemoresistance in lung cancer and is reversed by the membrane-permeable chelator MiADMSA.","authors":"Hannah L Richards, Steven J Bell, Katherine E V Deck, Anaïs M T Y Wiech, Emma Tarrant, Carissa M Lloyd, Juan A Aguilar, Dan Gelvan, William D G Brittain, Patricia A J Muller","doi":"10.1038/s41420-026-03222-8","DOIUrl":"10.1038/s41420-026-03222-8","url":null,"abstract":"<p><p>Elevated levels of transition metals are a common feature of solid tumours and are associated with poor clinical outcomes. However, tumour cells are exposed to complex metal mixtures rather than individual ions, and the functional consequences of such multi-metal exposure remain poorly defined. Here, we show that subtoxic combinations of metals cooperate to drive robust chemoresistance in lung cancer cells. This phenotype is not recapitulated by any single metal, demonstrating that resistance arises from coordinated multi-metal activity rather than individual metal effects. We further find that endogenous metal pools contribute to this response, and that metal-induced reactive oxygen species (ROS) are required but not sufficient, indicating that additional metal-dependent signalling mechanisms underpin chemoresistance. Because resistance emerges from collective metal activity, targeting individual metals fails to restore chemosensitivity. We therefore evaluated a pan-metal chelation strategy and identify monoisoamyl dimercaptosuccinic acid (MiADMSA) as a membrane-permeable chelator capable of targeting intracellular metal pools. Using complementary biochemical and cellular approaches, including a fluorinated derivative to track intracellular activity, we demonstrate that MiADMSA acts within cells to reverse metal-induced chemoresistance across multiple lung cancer models. Importantly, MiADMSA suppresses tumour growth in metal-exposed xenografts. Together, these findings identify multi-metal cooperation as a previously underappreciated driver of chemoresistance and establish intracellular pan-metal chelation as a potentially actionable strategy to restore chemotherapy sensitivity.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396193","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":"Unlocking the ferroptotic window: Lipidomic rewiring and metabolic addiction in EMT-driven breast cancer resistance.","authors":"Jian Lu, Chrysa Filippopoulou, Junjie Sun, Pengtao Hu, Chaoyue Pan, Xiaoyan Wu, Xidong Gu, Xiaohong Xie, Qijin Shu, Georgios Giamas","doi":"10.1038/s41420-026-03217-5","DOIUrl":"10.1038/s41420-026-03217-5","url":null,"abstract":"<p><p>Breast cancer (BC) continues to pose a substantial clinical challenge due to acquired resistance induced by epithelial-mesenchymal transition (EMT). Nevertheless, this adaptive evolution, which frequently takes the form of a highly plastic, partial EMT (p-EMT) state, induces a profound lipidomic reconfiguration and iron dysregulation, thereby inadvertently revealing a targetable metabolic vulnerability: ferroptosis. In this Perspective, we outline the hierarchical molecular logic that governs this susceptibility, emphasizing the manner in which progressive p53 mutations (ranging from loss-of-function to gain-of-function) transform p-EMT cells from passive sensitization to an extreme \"metabolic addiction.\" We argue that conventional \"occupancy-driven\" kinase inhibitors are unable to eliminate these resistant populations because they are unable to dismantle the essential non-catalytic scaffolding functions of core EMT-induced kinases (EIKs). As a result, we suggest a paradigm shift toward a chemical biology approach that is \"event-driven.\" The p-EMT infrastructure can be irreversibly destroyed and resistant cells can be compelled to undergo catastrophic lipid peroxidation by deploying proteolysis targeting chimeras (PROTACs) against concealed scaffold super-hubs, particularly AXL and lemur tail kinase 3 (LMTK3), which are indispensable for stabilizing the hybrid p-EMT infrastructure. Additionally, we investigate the spatiotemporal modulation of this synthetic lethal axis by the tumor microenvironment (TME) through matrix mechanics and extracellular vesicles (EVs). Ultimately, we suggest a multimodal liquid biopsy strategy that couples specific oxidized phospholipid signatures with circulating tumor DNA (ctDNA) kinetics to precisely monitor in vivo ferroptotic events. This approach offers a transformative roadmap for eradicating minimal residual disease (MRD) and surmounting BC dormancy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387269","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}