Apoptosis最新文献

{"title":"Copper dysregulation in cardiometabolic disease: copper deficiency versus cuproptosis","authors":"Vincent Kawuribi,&nbsp;Chido Tauro,&nbsp;Praise Audax Rukonge,&nbsp;Joyce Kangwa Mwanza,&nbsp;Martin Mussa Madadi,&nbsp;Joseph Adu-Amankwaah","doi":"10.1007/s10495-026-02390-3","DOIUrl":"10.1007/s10495-026-02390-3","url":null,"abstract":"<div><p>Copper is an essential micronutrient required for mitochondrial respiration, antioxidant defense, and metabolic homeostasis. Accumulating evidence demonstrates that dysregulated copper handling, including deficiency, redistribution, or overload, is a reproducible feature of multiple cardiometabolic disorders, including heart failure, diabetes mellitus, obesity, and NAFLD/MASLD. Human, animal, and cellular studies consistently implicate altered copper trafficking and compartmentalization in mitochondrial dysfunction, oxidative stress, and tissue remodeling across these conditions. The recent identification of cuproptosis, a copper-dependent form of regulated cell death characterized by mitochondrial copper binding to lipoylated tricarboxylic acid cycle enzymes, has expanded mechanistic understanding of copper toxicity in cancer. However, the defining molecular hallmarks of canonical cuproptosis, including lipoylated protein aggregation, iron–sulfur cluster loss, and respiration-dependent cell death, have not yet been demonstrated in vivo in cardiometabolic tissues. Accordingly, cuproptosis is discussed here as a testable mechanistic hypothesis rather than an established driver of cardiometabolic pathology. In this review, we synthesize current evidence for copper dysregulation in cardiometabolic disease and carefully distinguish established copper-dependent pathology from speculative cuproptotic mechanisms. We explicitly address the apparent paradox that the cardiac tissue context in cardiometabolic disease is dominated by a copper-deficient phenotype, which is the opposite of the mitochondrial copper-loading state required for canonical cuproptosis, and reconcile this through the concept of intracellular copper redistribution and tissue-selective susceptibility. We evaluate clinical and preclinical studies of copper-modulating therapies with attention to tissue specificity and safety, and we outline a framework for rigorously testing cuproptosis in vivo using convergent molecular, functional, and clinical criteria. Together, this review clarifies what is known about copper biology in metabolic disease and defines the experimental standards required to determine whether cuproptosis contributes to these conditions.</p><h3>Graphical abstract</h3><p>Copper dysregulation is a reproducible feature ofcardiometabolic disease, where functional copper deficiency and impairedintracellular copper handling drive mitochondrial dysfunction, oxidativestress, and tissue remodeling. Canonical cuproptosis, defined by lipoylatedprotein aggregation and Fe–S cluster loss following mitochondrial Cu⁺accumulation, is established in cancer but lacks direct in vivo evidence incardiometabolic tissues. This schematic distinguishes established copperdependentpathology from hypothesized cuproptotic mechanisms,highlighting their parallel and context-dependent nature.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359046","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":"GPx6 downregulation drives ferroptosis in Kashin-Beck disease chondrocytes via the SLC7A11/GPx4 axis","authors":"Yinan Liu,&nbsp;Jie Li,&nbsp;Meng Zhang,&nbsp;Ying Zhang,&nbsp;Mengying Wang,&nbsp;Rui Wang,&nbsp;Xiaoming Zhao,&nbsp;Pinglin Yang,&nbsp;Jinghong Chen,&nbsp;Jian Sun","doi":"10.1007/s10495-026-02389-w","DOIUrl":"10.1007/s10495-026-02389-w","url":null,"abstract":"<div><p>Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by chondrocyte death and extracellular matrix (ECM) degradation; however, the underlying molecular mechanisms remain poorly understood. This study aimed to explore whether glutathione peroxidase 6 (GPx6) is involved in regulating ferroptosis and matrix degradation in KBD cartilage injury. In articular cartilage from children with KBD, GPx6 expression was markedly reduced, particularly in the deep zone where chondrocyte death and matrix loss were most severe. Similarly, downregulation of GPx6 was observed in a T-2 toxin‑induced rat model and in C28/I2 chondrocytes, accompanied by decreased COL2A1 and ACAN levels and increased expression of MMP13 and ADAMTS4. Molecular docking indicates a potential interaction between T-2 toxin and GPx6. <i>Gpx6</i> knockout mice exhibited signs of ECM degradation in articular cartilage, along with an enhanced susceptibility to T-2 toxin exposure. Mechanistically, <i>Gpx6</i> deficiency led to elevated MDA levels, reduced SOD activity and GSH/GSSG ratio, as well as mitochondrial shrinkage, cristae loss, and lipid peroxidation. Knockdown of <i>GPX6</i> suppressed the expression of SLC7A11, SLC3A2, and GPx4, while Ferrostatin‑1 partially reversed these ferroptosis‑related alterations but failed to restore GPx6 expression. Conversely, overexpression of <i>GPX6</i> partially restored the function of the SLC7A11/GPx4 axis, improved redox balance, attenuated mitochondrial lipid peroxidation, and mitigated matrix degradation. Collectively, these findings suggest that downregulation of GPx6 may be closely associated with ferroptosis in KBD chondrocytes, and that GPx6 may serve as a potential upstream regulator of this process. Furthermore, dysregulation of the GPx6‑SLC7A11/GPx4 pathway may also be involved in the pathological process of cartilage injury in KBD.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10495-026-02389-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359026","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":"Microglial tunneling nanotubes: an intercellular transfer facilitating mitochondrial dysfunction and neuroinflammation in experimental cerebral malaria","authors":"Yan Shen,&nbsp;Yi Wang,&nbsp;Chao Yang,&nbsp;Jun Wang,&nbsp;Yuxiao Huang,&nbsp;Qinghao Zhu,&nbsp;Ganze Li,&nbsp;Tong Li,&nbsp;Jiayi Sun,&nbsp;Jie Ren,&nbsp;Xiaolin Chen,&nbsp;Shuhan Xing,&nbsp;Sijia Wen,&nbsp;Yinghui Li,&nbsp;Jiao Liang,&nbsp;Ya Zhao","doi":"10.1007/s10495-026-02370-7","DOIUrl":"10.1007/s10495-026-02370-7","url":null,"abstract":"<div><p>Cerebral malaria (CM), the most severe neurological manifestation of <i>Plasmodium</i> infection, is characterized by microglial activation that plays a pivotal role in initiating pathogenic neuroinflammatory cascades. Tunneling nanotubes (TNTs) are dynamic F-actin-based intercellular connections which transfer mitochondria and pathogenic factors. Although TNTs have been implicated in various neuropathological conditions, their precise involvement in CM pathogenesis, particularly in relation to microglial activation, remains undefined. In this study, single-cell RNA-sequencing (scRNA-seq) revealed significant dysregulation of TNT-associated genes and actin cytoskeleton pathway remodeling in microglia of ECM model. In vitro studies demonstrated that <i>Plasmodium</i>-infected red blood cells (pRBCs)-stimulated primary microglia formed extensive F-actin-rich tunneling nanotubes, which mediated the bidirectional transfer for mitochondria and facilitated intercellular trafficking of lysosomal contents and malarial pigment. These TNT-mediated intercellular communication amplified microglial activation, as evidenced by: (i) lipid peroxidation, (ii) mitochondrial dysfunction, and (iii) autophagosome (LC3⁺) accumulation. This process further amplifies neuroinflammation through TNFα/IL-6 secretion and expansion of CD45^high microglial populations. Pharmacological TNT inhibition restores microglial homeostasis in ECM model. In conclusion, TNTs mediate neuroinflammation in the ECM model by transferring mitochondria and malarial pigment between microglia. Although mitochondrial transfer may transiently support cellular homeostasis, progressive malarial pigment accumulation triggers lipid metabolism dysregulation and amplified neuroinflammation. Inhibiting TNTs formation attenuates microglial hyperactivation, highlighting targeted regulation of TNT-mediated intercellular communication as a potential therapeutic approach for CM-associated neuropathology.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366674","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":"Interplay between ischemia–reperfusion and metabolic reprogramming","authors":"Lei Duan,&nbsp;Hui Ao,&nbsp;Lizhou Song,&nbsp;Haoling Zhang,&nbsp;Yan Liao,&nbsp;Wangzheqi Zhang","doi":"10.1007/s10495-026-02392-1","DOIUrl":"10.1007/s10495-026-02392-1","url":null,"abstract":"<div><p>A common pathological process associated with acute organ injury, which is closely connected to metabolic reprogramming, is ischemia–reperfusion injury (IRI). Ischemia leads to decreased oxygen and substrate availability, with rapid activation of energy-sensing pathways, increased dependence on glycolysis, and predisposition of mitochondria to later oxidative injury. Reperfusion involves the rapid restoration of blood supply, with oxidative stress, inflammatory responses and remodeling of metabolic networks. Here, we summarize current evidence for the bidirectional interaction between IRI and metabolic reprogramming by organizing conceptual topics around glucose metabolism, lipid remodeling, amino acid metabolism and tricarboxylic acid cycle (TCA)-centered substrate convergence. Here, we focus on metabolic events according to the ischemic and reperfusion stages, from the early to the delayed phase, including succinate accumulation, reactive oxygen species (ROS) generation via reverse electron transport, mitochondrial quality control, immunometabolic remodeling, as well as apoptosis, ferroptosis, pyroptosis and post-translational modifications. In addition, recent advances in metabolic biomarkers, experimental models and novel therapeutic strategies are highlighted. Recent evidence suggests that metabolic reprogramming is not simply a passive response to IRI, but an active regulatory process that controls the initiation and amplification of injury, as well as its resolution. A metabolomic framework within a time-staged and cell death-centered context may inform more clinically useful biomarkers and intervention windows for IRI.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359111","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":"CRKL amplification synergizes with mechanical stress-induced signaling to dually activate YAP oncogenic pathways, driving plantar melanoma progression","authors":"Jiashe Chen,&nbsp;Liang Li,&nbsp;Ruoqi Wang,&nbsp;Fei Wu,&nbsp;Nanhui Wu,&nbsp;Yongyi Xie,&nbsp;Wei Tan,&nbsp;Yun Bai,&nbsp;Shuyi Liu,&nbsp;Qi Yu,&nbsp;Yueyi Zhu,&nbsp;Mingyuan Xu,&nbsp;Xiaoxiang Xu,&nbsp;Yeqiang Liu","doi":"10.1007/s10495-026-02383-2","DOIUrl":"10.1007/s10495-026-02383-2","url":null,"abstract":"<div><p>Acral melanoma (AM) is the most common subtype of melanoma in non-Caucasian populations, typically arising in weight-bearing areas of the sole. Currently, the majority of patients lack effective targeted therapeutic drugs. V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), an adaptor protein, plays a pivotal role in the tumorigenesis and progression of various cancers. However, its function in the development of plantar acral melanoma remains unclear. In this study, clinical data and bioinformatic analyses reveal that CRKL is highly expressed in acral melanoma and is closely associated with Yes-associated protein (YAP) activity. Mechanistic studies further demonstrate that CRKL directly interacts with YAP, suppressing its ubiquitination and thereby preventing its proteasomal degradation. In addition, CRKL inhibits autophagy, further reducing YAP protein degradation. Notably, mechanical loading from weight-bearing activity is found to activate the YAP signaling pathway. Therefore, CRKL and mechanical stress synergistically to enhance YAP pathway activation, ultimately driving the initiation and progression of plantar melanoma. In conclusion, this study identifies CRKL as an oncogenic factor in plantar melanoma, elucidates the molecular basis underlying the predilection of this melanoma subtype for weight-bearing sites, and highlights CRKL as a potential therapeutic target for the treatment of plantar melanoma.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300693","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":"Apoptotic bodies in bone homeostasis and skeletal disease: biology and therapeutic implications","authors":"Yuhang Xi,&nbsp;Ying Qu,&nbsp;Ziyang Zhang,&nbsp;Jianzhong Xu,&nbsp;Fei Luo,&nbsp;Ce Dou","doi":"10.1007/s10495-026-02386-z","DOIUrl":"10.1007/s10495-026-02386-z","url":null,"abstract":"<div><p>Bone is among the most apoptotically active tissues in the body. During remodeling, repair, and disease, dying osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, and injury-associated cells release apoptotic bodies (ABs) that retain parent-cell-derived cargo and surface ligands. These vesicles are increasingly viewed not only as debris for efferocytic clearance but also as source-specific signalling units that shape skeletal cell fate, immune activity, mineralization, and repair. This review integrates current evidence for ABs across skeletal homeostasis and disease. We first define ABs within the broader extracellular vesicle landscape, emphasizing vesicle heterogeneity, isolation and characterization challenges, and terminology boundaries. We then examine AB sources and recipient interfaces, including osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, platelet-derived ABs in injury repair, macrophages, osteoclast phagocytes, chondrocytes, and bone lining cells. We further discuss how dysregulated AB signalling contributes to osteoporosis, osteoarthritis, and bone metastasis, as well as alveolar bone destruction, aging-related bone loss, osteochondral mineralization, and bone injury repair. We highlight therapeutic implications, including AB-based or AB-inspired strategies, the cathepsin K (CTSK)-responsive self-assembling peptide nanoparticle OsteoSAVE for in vivo generation of osteoclast-derived ABs, and the hypothesis that antiresorptive therapies may reshape osteoclast-derived AB (OC-AB) production. We also identify unresolved translational questions, including AB lifespan, circulation, source attribution, and direct human validation.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148281805","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":"Apoptosis execution is spatially regulated","authors":"Nevena Milivojević Dimitrijević,&nbsp;Ana Mirić,&nbsp;Tijana Đukić,&nbsp;Ivica Petrović,&nbsp;Ana Kesić,&nbsp;Vladimir Jurišić,&nbsp;Luka Dragačević,&nbsp;Marko N. Živanović,&nbsp;Nenad Filipović","doi":"10.1007/s10495-026-02385-0","DOIUrl":"10.1007/s10495-026-02385-0","url":null,"abstract":"<div><p>Three-dimensional (3D) cell culture models are increasingly used in biomedicine, while two-dimensional (2D) systems represent a simplified approach with limited intercellular interactions and no spatial organization. The aim of this work was to compare the response of tumor cells to cytotoxic chemical complexes in 2D and 3D conditions, with a special focus on apoptosis. The results showed a pronounced paradox: although proapoptotic markers (Bax/Bcl-2 ratio and caspase-3) were higher in the 2D system, the phenotypic outcome indicated a higher frequency of late apoptosis in 3D conditions, with a lower percentage of viable cells. These findings indicate that molecular markers do not directly reflect the outcome of cell death, but the apoptotic response depends on the spatial context. The mathematical model offered additional quantitative insight that may help to contextualize these differences, suggesting localized hypoxic and metabolic adaptation in 3D systems. In conclusion, in HCT-116 treated with Au(III) complexes, 2D and 3D models represent qualitatively different modes of response. These observations support the hypothesis that apoptosis execution is shaped by spatial context, pending validation in additional cell lines and platforms.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275665","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":"USP9X regulates copper-induced CASP9/CASP3/GSDME-dependent pyroptosis by deubiquitinating JAK1","authors":"Huaduan Zi,&nbsp;Hengcheng Tang,&nbsp;Xiaoxi Yang,&nbsp;Xiaojin Li,&nbsp;Yanmeng Li,&nbsp;Anjian Xu,&nbsp;Qin Ouyang,&nbsp;Sisi Chen,&nbsp;Pingping He,&nbsp;Yanling Li,&nbsp;Qianyu Zhu,&nbsp;Bei Zhang,&nbsp;Wei Zhang,&nbsp;Xiaojuan Ou,&nbsp;Liying Sun,&nbsp;Donghu Zhou,&nbsp;Jian Huang","doi":"10.1007/s10495-026-02379-y","DOIUrl":"10.1007/s10495-026-02379-y","url":null,"abstract":"<div><h3>Purpose</h3><p>Wilson disease (WD) is characterized by hepatic injury caused by copper accumulation; however, the underlying molecular mechanisms remain incompletely understood. This study aims to investigate whether copper overload induces pyroptosis in WD and to elucidate the role of USP9X-mediated JAK1 deubiquitination in this process.</p><h3>Methods</h3><p>Integrated transcriptomic, proteomic, and ubiquitinomic analyses were performed on liver tissues from WD patients and ATP7B-knockout cellular models. The involvement of the JAK1/STAT1 signaling pathway, the CASP9/CASP3/GSDME axis, and USP9X-mediated deubiquitination was further investigated using pharmacological inhibition as well as gene knockout and knockdown approaches, and the findings were subsequently validated in Atp7b^−/− mouse models.</p><h3>Results</h3><p>Copper overload markedly activated the JAK1/STAT1 signaling pathway, enhanced reactive oxygen species (ROS) production, and triggered activation of CASP9 and CASP3, resulting in GSDME cleavage and a switch from hepatocyte apoptosis to pyroptosis. Mechanistically, copper upregulated USP9X expression, which mediated the deubiquitination of JAK1 at lysine 249, thereby stabilizing JAK1 and enhancing downstream signaling cascade. Pharmacological or genetic inhibition of JAK1/STAT1 pathway or GSDME significantly attenuated pyroptosis and alleviated liver injury in WD mouse models, even in the presence of persistent copper accumulation.</p><h3>Conclusions</h3><p>USP9X deubiquitinates JAK1, thereby promoting copper-induced CASP9/CASP3/GSDME-dependent pyroptosis and liver injury in WD. Targeting the USP9X/JAK1 axis may represent a promising therapeutic strategy for WD.</p><h3>Graphical abstract</h3><p>Copper activates the JAK1/STAT1 pathway, leading to ROS production and apoptosis, which in turn induces GSDME-dependent pyroptosis and hepatic injury. Copper also upregulates USP9X expression, thereby stabilizing JAK1 through deubiquitination and further enhancing JAK1/STAT1 signaling and pyroptosis.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275791","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":"Retiring M1/M2: a view from the succinate receptor","authors":"Franco Grimolizzi","doi":"10.1007/s10495-026-02382-3","DOIUrl":"10.1007/s10495-026-02382-3","url":null,"abstract":"","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275809","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":"Heteronemin suppresses chemoresistant oral squamous cell carcinoma cells through ROS-mediated apoptosis and cuproptosis-associated mitochondrial stress","authors":"Chiung-Wei Huang,&nbsp;Fan-Li Lin,&nbsp;Chun-Feng Chang,&nbsp;Hsiao-Hsuan Huang,&nbsp;Wan-Ju Wu,&nbsp;Hui-Min Chang,&nbsp;Mei-Ying Lin,&nbsp;Jue-Liang Hsu,&nbsp;Shih-Ya Hung,&nbsp;Chien Hsing Lee","doi":"10.1007/s10495-026-02380-5","DOIUrl":"10.1007/s10495-026-02380-5","url":null,"abstract":"<div><p>Chemoresistance remains a major barrier in treating oral squamous cell carcinoma (OSCC). This study investigated whether the marine-derived sesterterpenoid heteronemin (HET) suppresses chemoresistant OSCC (SAS-CR) cells and elucidated its underlying mechanisms. HET dose- and time-dependently reduced SAS-CR viability, inhibited clonogenic growth, and exhibited stronger cytotoxicity than cisplatin or 5-fluorouracil. Furthermore, HET induced S-phase arrest by downregulating proliferation and cell-cycle proteins (PCNA, c-Myc, cyclin A, cyclin D3, CDK4, and CDK6). Concurrently, it triggered intrinsic apoptosis, characterized by mitochondrial depolarization, upregulated cleaved caspase-3/PARP and Bax, and downregulated Bcl-2. This caspase-dependent apoptosis was partially reversed by pan-caspase inhibitor Z-VAD-FMK. Transcriptomic profiling linked these phenotypes to metabolic stress, revealing alterations in the tricarboxylic acid cycle, mitochondrial respiration, and copper homeostasis. Consistently, HET elevated intracellular Cu²⁺ levels and reduced FDX1, SDHB, and lipoylated DLST/DLAT protein expression-cytotoxic effects that were attenuated by the copper chelator tetrathiomolybdate (TTM). Additionally, HET increased reactive oxygen species (ROS) production, whereas ROS scavenger N-acetylcysteine (NAC) attenuated HET-induced apoptosis and restored cuproptosis-related markers. In a zebrafish model, HET demonstrated negligible toxicity while reducing tumor-associated fluorescence and FDX1 expression. Collectively, HET effectively suppresses chemoresistant OSCC through coordinated ROS-dependent apoptosis and cuproptosis-associated mitochondrial stress, supporting its development as a therapeutic candidate for refractory OSCC.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 7","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275820","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}