Apoptosis最新文献

{"title":"Microbiota-derived 4-HPAA alleviates Crohn’s disease by stabilizing SIRT1 and reprogramming macrophage immunometabolism","authors":"Chao Cheng,&nbsp;Shaoqi Cheng,&nbsp;Wenliang Jiang,&nbsp;Shuqiang Fu,&nbsp;Yangjie Shang,&nbsp;Xiufang Tang,&nbsp;Jie Zhao,&nbsp;Honggang Wang","doi":"10.1007/s10495-026-02417-9","DOIUrl":"10.1007/s10495-026-02417-9","url":null,"abstract":"<div><p>Crohn’s disease (CD) is characterized by mucosal immune dysregulation, gut microbiota disturbance, and epithelial barrier dysfunction. This study investigated whether an Aronia berry polyphenol-rich diet attenuates CD-related intestinal inflammation through microbiota-derived metabolic signals. IL-10^−/− and TNBS-induced colitis mouse models were used to evaluate the effects of dietary intervention, bacterial strain supplementation, and candidate metabolite administration. Integrated metagenomic, metabolomic, and transcriptomic analyses were combined with in vivo and in vitro mechanistic experiments to identify diet-responsive microbial taxa, metabolites, and host regulatory pathways. This diet alleviated colitis, reduced mucosal injury, and improved epithelial barrier integrity. Multi-omics analyses identified <i>Flavonifractor plautii</i> enrichment and increased microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) levels as major diet-associated changes. <i>F. plautii</i> supplementation was associated with increased 4-HPAA production, while 4-HPAA administration partially reproduced the intestinal protective phenotype in vivo. In macrophages, 4-HPAA suppressed pro-inflammatory activation and promoted oxidative metabolic remodeling. Mechanistically, 4-HPAA stabilized SIRT1 by limiting ubiquitination-mediated proteasomal degradation, thereby activating SIRT1–PGC-1α signaling. Myeloid SIRT1 deficiency attenuated the effects of 4-HPAA on macrophage polarization, inflammatory cytokine expression, and epithelial barrier-associated proteins. These findings identify a diet-associated microbial metabolite pathway involving <i>F. plautii</i>, 4-HPAA, and SIRT1 signaling, linking polyphenol-rich dietary intervention to macrophage immunometabolic regulation and intestinal barrier protection. This microbial metabolite-centered mechanism may provide insight into nutritional intervention strategies for CD-related intestinal inflammation.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807960","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":"Revisiting tumor immunogenicity through the lens of mutant p53: Implications for cancer immunotherapy","authors":"Sourio Chakraborty,&nbsp;Sumon Mukherjee,&nbsp;Subhajit Ghosh,&nbsp;Udit Basak,&nbsp;Sumoyee Mukherjee,&nbsp;Arghya Adhikary,&nbsp;Gaurisankar Sa,&nbsp;Tanya Das","doi":"10.1007/s10495-026-02409-9","DOIUrl":"10.1007/s10495-026-02409-9","url":null,"abstract":"&lt;div&gt;&lt;p&gt;The efficacy of cancer immunotherapy depends on the inherent immunogenicity of tumor cells, which is their ability to display recognizable antigens and stimulate effective immune responses. However, the immunogenic landscape of cancer is not static; it evolves through cancer immunoediting, a dynamic process that refines tumor antigenicity and sculpts immune evasion mechanisms. This immunogenic reprogramming often dictates therapeutic responsiveness, with many tumors acquiring immune resistance through defective antigen presentation, impaired interferon signaling, and the establishment of immunosuppressive microenvironments. Within this complex interplay, mutant p53 (mut-p53) has emerged as a pivotal regulator of tumor immunogenicity. Beyond its canonical oncogenic functions, gain-of-function (GOF) and other p53 mutants modulate antigen processing, repress immune-stimulatory pathways, upregulate immune-checkpoint (IC) molecules, and remodel the tumor microenvironment (TME) to favor immune escape. Paradoxically, their structural instability and aberrant accumulation generate tumor-specific neoepitopes, rendering mut-p53 a potential tumor-specific antigen (TSA) with both immunogenic and immunosuppressive properties. Such dual propensity of mut-p53 positions it as a central architect of immune editing and a critical predictor of immunotherapy outcomes. This review amalgamates growing molecular and clinical evidences to elucidate how mut-p53 regulates the immunogenic continuum of malignancies and contributes to foster immunotherapy resistance. Furthermore, this review emphasizes the novel therapeutic prospects of hotspot &lt;i&gt;TP53&lt;/i&gt; mutations in either generating neoantigen vaccines, T cell receptor (TCR)-based therapies, or by pharmacological targeting of mut-p53 to restore immune surveillance, improve antigen presentation, and synergize with immune-checkpoint blockade (ICB). By bridging the conceptual frameworks of tumor immunogenicity and oncogenic signaling, current review highlights mut-p53 as a promising context-dependent biomarker whose predictive value is determined by its interaction with established molecular and immunological determinants of tumor immunogenicity, immune escape, therapeutic resistance, and tumor evolution; thus underscoring its promise as both a biomarker and a therapeutic target in crafting next-generation precision cancer immunotherapy strategies.&lt;/p&gt;&lt;h3&gt;Graphical abstract&lt;/h3&gt;&lt;div&gt;&lt;figure&gt;&lt;div&gt;&lt;div&gt;&lt;picture&gt;&lt;source&gt;&lt;img&gt;&lt;/source&gt;&lt;/picture&gt;&lt;/div&gt;&lt;/div&gt;&lt;/figure&gt;&lt;/div&gt;&lt;p&gt;Dual immunological identity of mutant p53 (mut-p53) functions as the context-dependent determinant of tumor immunogenicity and cancer immunotherapy outcome. Mut-p53 exerts a context-dependent influence on anti-tumor immunity by functioning as both a driver of immune evasion and a potential source of tumor-specific neoepitopes. With the advancement of tumor stages, mut-p53 promotes reduced antigen processing and presentation, increased immune checkpoi","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783128","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":"Endothelial cell heterogeneity drives angiogenesis in endometriosis: mechanisms and emerging organoid-based models","authors":"Jingjing Xu,&nbsp;Yadan Tan,&nbsp;Ziteng Huang,&nbsp;Xiran Wang,&nbsp;Lihong Song,&nbsp;Jinshan Xing,&nbsp;Rong Li,&nbsp;Jingyan Yi","doi":"10.1007/s10495-026-02427-7","DOIUrl":"10.1007/s10495-026-02427-7","url":null,"abstract":"<div><p>Endometriosis (EMs) is characterized by the establishment and persistence of ectopic lesions, a process fundamentally dependent on aberrant angiogenesis. Endothelial cells (ECs) play a central role in this process; however, accumulating evidence indicates that ECs are not a homogeneous population but comprise multiple subtypes with distinct molecular signatures and functional states, including quiescent, proliferative, hormone-responsive and inflammation-associated phenotypes. The initiation and maintenance of pathological angiogenesis in EMs are coordinately regulated by hormonal signaling, inflammatory responses and immune modulation, which collectively determine vascular remodeling and lesion sustainability. Despite significant advances, mechanistic insights into EMs-associated angiogenesis have been limited by the lack of physiologically relevant experimental models. Conventional two-dimensional culture systems fail to recapitulate the complex three-dimensional cellular interactions, whereas animal models are constrained by interspecies differences. Recent progress in stem cell biology, extracellular matrix (ECM) engineering and microfluidic technologies has enabled the development of organoid-based platforms that more faithfully reconstruct the EMs microenvironment. When integrated with functional biomaterials possessing tunable mechanical properties and bioactivity, these systems allow precise modulation of endothelial behaviors, including proliferation, migration and lumen formation, through controlled delivery of angiogenic cues. In this Review, we summarize recent advances in biomaterial-supported organoid systems for dissecting endothelial cell heterogeneity and its contribution to aberrant angiogenesis in EMs. We further discuss their emerging roles in mechanistic studies and the development of targeted therapeutic strategies.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782953","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":"APOM-associated inflammation and apoptosis in stroke-exacerbated myocardial infarction: implications for brain–heart interactions","authors":"Min Wang,&nbsp;Dongmei Di,&nbsp;Yongxiang Qian,&nbsp;Bin Wang,&nbsp;Xiaoying Zhang","doi":"10.1007/s10495-026-02430-y","DOIUrl":"10.1007/s10495-026-02430-y","url":null,"abstract":"<div><p>Brain–heart syndrome (BHS) describes cardiac dysfunction secondary to central nervous system injury, with acute ischemic stroke (AIS) serving as a critical driver that exacerbates myocardial infarction (MI). This study aimed to elucidate the role of Apolipoprotein M (APOM) in stroke-aggravated MI and to explore its underlying systemic and molecular mechanisms. Clinical data were analyzed to evaluate the correlation between stroke and MI. A combined mouse model of middle cerebral artery occlusion (MCAO) and MI was established to assess neurological and cardiac injury. Quantitative proteomics and Weighted Gene Co-expression Network Analysis (WGCNA) were employed to screen key differentially expressed proteins. The role of APOM in myocardial injury was validated using APOM-knockout (KO) mice. Furthermore, nuclear-cytoplasmic fractionation, immunofluorescence, and Western blot were performed to investigate its effects on the Saa1 and NF-κB signaling, NLRP3-related inflammatory signaling pathway, and lipid metabolism pathways. Clinical analysis indicated that stroke is a significant risk factor for MI (OR = 4.5). In the mouse model, MCAO significantly exacerbated post-MI electrocardiographic abnormalities, myocardial inflammatory response, while elevating circulating levels of cTnT and IL-1β. Proteomics identified a significant downregulation of APOM in the heart, brain, and serum post-stroke, a trend consistent with observations in AIS patients. Further experiments revealed that APOM deficiency markedly worsened cardiac conduction disturbances, histological damage, and inflammatory responses in MI mice. Mechanistically, the loss of APOM upregulates the acute-phase protein Saa1, triggers NF-κB phosphorylation and nuclear translocation, and enhances inflammatory signaling related to inflammasomes, while simultaneously mediating cytokine release from cardiomyocytes. Concurrently, APOM deficiency led to a significant decrease in sphingosine-1-phosphate (S1P) and also caused myocardial lipid droplet accumulation and metabolite changes. Additionally, the loss of APOM increased the expression of D-dimer and fibrinogen family proteins. Our findings suggest that APOM is a potential cardioprotective agent post-AIS. Downregulation of APOM may exacerbate myocardial injury after MI by elevating Saa1 expression, activating the NF-κB pathway and the inflammasome-mediated signaling, and inducing lipid metabolic disorders and coagulation-associated alterations. APOM may represent a potential therapeutic target for the intervention of brain–heart syndrome.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782954","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":"Disrupting KRAS–AGO2 interaction: a dual-pronged strategy to sensitize chemo-immunotherapy in KRAS-mutated colorectal cancer","authors":"Jingyi Xie,&nbsp;Simeng Wang,&nbsp;Juan Liu,&nbsp;Yan Zhang,&nbsp;Haixiao Zhu,&nbsp;Rongrong Cui,&nbsp;Yao Yao,&nbsp;Wei Yu,&nbsp;Peng Hou","doi":"10.1007/s10495-026-02429-5","DOIUrl":"10.1007/s10495-026-02429-5","url":null,"abstract":"<div><p><i>KRAS</i> mutations are among the most common genetic alterations in colorectal cancer (CRC) and are strongly linked to poor prognosis and therapeutic resistance. However, current treatments targeting KRAS-mutated CRC have shown limited clinical efficacy. Argonaute 2 (AGO2) is a critical component in microRNA (miRNA)-mediated gene silencing complex, which is involved in the maturation of miRNAs and the regulation of target genes. It has been reported that mutated KRAS can interact with AGO2 and impair its function, thereby amplifying the oncogenic potency of mutant KRAS and accelerating tumor progression. To explore the therapeutic implications of this interaction, we developed a peptide inhibitor and engineered peptide-gold nanoparticles (Au-pep) that specifically disrupted KRAS-AGO2 interaction, which dramatically attenuated the malignant phenotype of KRAS-mutated CRC cells. Mechanistically, Au-pep-mediated disruption of the KRAS-AGO2 complex led to partial restoration of the miRNA expression landscape, with let‑7c‑5p emerging as the most significantly up‑regulated effector. As a result, restored let-7c-5p caused a significant down-regulation of key oncogenic drivers (KRAS, c-Myc and Bcl2) to suppress the growth of KRAS-mutated CRC cells and induce their apoptosis. Furthermore, this miRNA restoration conferred dual therapeutic benefits by sensitizing KRAS-mutated CRC cells to 5-fluorouracil (5-FU) via ABCC5 repression and augmenting immunotherapy responsiveness via PD-L1 down-regulation. Our findings, taken together, delineate a new therapeutic paradigm with significant translational potential for improving clinical outcomes in this recalcitrant patient population.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782952","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":"Programmed cell death in kidney disease: integrated crosstalk among ferroptosis, pyroptosis, apoptosis, and cuproptosis","authors":"Jiajun Sang,&nbsp;Zhentao Guo,&nbsp;Chengxia Kan,&nbsp;Fang Han,&nbsp;Xiaodong Sun,&nbsp;Kexin Zhang","doi":"10.1007/s10495-026-02428-6","DOIUrl":"10.1007/s10495-026-02428-6","url":null,"abstract":"<div><p>Programmed cell death (PCD) is a central determinant of kidney injury, maladaptive repair, and chronic progression. Beyond classical apoptosis, the identification of ferroptosis, pyroptosis, and cuproptosis has expanded the conceptual framework of renal pathophysiology by linking cell fate decisions to redox imbalance, inflammatory signaling, mitochondrial metabolism, and metal ion homeostasis. Ferroptosis is driven by iron-dependent phospholipid peroxidation and impaired antioxidant defenses; pyroptosis is mediated by inflammasome activation, gasdermin pore formation, and cytokine release; apoptosis results from caspase-dependent cellular dismantling; and cuproptosis reflects copper-induced disruption of lipoylated tricarboxylic acid cycle proteins and mitochondrial proteostasis. Here, we propose a “metabolic crisis-cascade” framework, in which progressive disruption of energy metabolism, redox balance, and metal homeostasis acts as a unifying upstream mechanism linking multiple PCD pathways during kidney injury. In acute kidney injury (AKI), ferroptosis and pyroptosis contribute prominently to early tubular injury, whereas persistent apoptosis, recurrent ferroptotic stress, and emerging copper-dependent metabolic vulnerability contribute to chronic kidney disease (CKD), diabetic kidney disease, glomerular injury, inflammation, and fibrosis. These pathways are interconnected through common stress signals, including reactive oxygen species accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, Nrf2/Keap1-dependent antioxidant responses, inflammasome activation, and metal dysregulation. Understanding their temporal and compartment-specific activation is essential for distinguishing adaptive responses from irreversible damage. Targeting lipid peroxidation, inflammasome signaling, mitochondrial stability, apoptosis regulation, and copper metabolism may provide complementary strategies for limiting renal injury and preventing AKI-to-CKD transition. Future studies integrating multiomics approaches and disease-stage-resolved models will be required to define actionable cell-death signatures and enable precision interventions in kidney disease.</p><h3>Graphical abstract</h3><p>Programmed cell death in kidney disease progression. The healthy kidney displays intact tubules and glomeruli. AKI is characterized by early ferroptosis, reflected by lipid peroxidation, and pyroptosis, reflected by cell swelling and cytokine release. CKD is characterized by tubular atrophy, fibrosis, recurrent ferroptotic stress, apoptosis, and emerging copper-dependent mitochondrial vulnerability.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782788","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":"Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation","authors":"Jie Xu,&nbsp;Mengting He,&nbsp;Jiayao Liu,&nbsp;Yuhui Li,&nbsp;Yajie Hu,&nbsp;Honghong Chen,&nbsp;Yuyu Zhang,&nbsp;Jun Chang,&nbsp;Xinhua Liu","doi":"10.1007/s10495-026-02418-8","DOIUrl":"10.1007/s10495-026-02418-8","url":null,"abstract":"<div><p>Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782789","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":"Targeting FAR1 to inhibit intestinal macrophage ferroptosis: repurposing irinotecan as a novel sepsis therapy","authors":"Haoyue Deng,&nbsp;Weifei Wang,&nbsp;Qinghui Li,&nbsp;Xinming Xiang,&nbsp;Yu Zhu,&nbsp;Zisen Zhang,&nbsp;Xiaowei Zhou,&nbsp;Yue Wu,&nbsp;Jie Zhang,&nbsp;Liangming Liu,&nbsp;Tao Li","doi":"10.1007/s10495-026-02419-7","DOIUrl":"10.1007/s10495-026-02419-7","url":null,"abstract":"<div><p>Intestinal barrier breakdown is a key driver of sepsis-related multiple organ dysfunction; however, the metabolic mechanisms underlying this process remain poorly understood. In this study, by integrating multiomic analysis with machine learning on clinical and experimental data, we identified fatty acyl-CoA reductase 1 (FAR1) as a critical regulator that promotes ferroptotic susceptibility in sepsis. FAR1 was markedly upregulated in septic macrophages, promoting polyunsaturated ether phospholipid remodeling and lipid peroxidation involving the ACSL4/GPX4 metabolic-regulatory network. We repurposed irinotecan as a FAR1-targeting compound through pharmacological sensitivity screening and subsequent validation. Beyond its canonical function as a topoisomerase I inhibitor, irinotecan exhibited a noncanonical activity by directly interacting with FAR1 in a Gly252-dependent manner. This interaction suppresses FAR1-associated ether lipid metabolic remodeling, thereby attenuating ferroptotic responses and preserving the “gatekeeper” function of intestinal macrophages. In preclinical sepsis models, low-dose irinotecan attenuated macrophage ferroptotic responses, restored mitochondrial integrity, alleviated intestinal barrier dysfunction, and improved survival. Our findings provide evidence supporting a “target–drug–mechanism” framework and highlight the potential repurposing of irinotecan as a host-directed therapeutic strategy for sepsis, particularly in contexts associated with elevated FAR1 expression.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 9","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10495-026-02419-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782241","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":"Metabolic cell death: ferroptosis, cuproptosis, and disulfidptosis as a unified framework for targeting metabolic vulnerabilities in disease","authors":"YaQi Li,&nbsp;SongYu Wang,&nbsp;GuangDong Liu,&nbsp;ChengXin Yin","doi":"10.1007/s10495-026-02416-w","DOIUrl":"10.1007/s10495-026-02416-w","url":null,"abstract":"<div><p>Resistance to apoptosis-targeted cancer therapies remains a major clinical hurdle. Ferroptosis, cuproptosis, and disulfidptosis represent typical forms of metabolic cell death that bypass classical apoptotic pathways, offering unprecedented opportunities to overcome such resistance. These three death modalities converge on a shared metabolic hub—the SLC7A11/cystine/GSH/NADPH axis—where disruption at different nodes steers the outcome toward ferroptosis, cuproptosis, or disulfidptosis. This interconnection is the foundation of our unified framework. While recent seminal reviews (Mao et al.) have established the conceptual framework integrating ferroptosis, cuproptosis, and disulfidptosis, the translational implementation of this framework remains fragmented. Here, we extend this established paradigm by providing a comprehensive, clinically actionable metabolic vulnerability atlas that not only systematically dissects the regulatory logic in both oncological and non-oncological settings but also, for the first time, proposes a bench-to-bedside bidirectional roadmap that prioritizes solutions for biomarker scarcity, systemic toxicity, and mechanistic heterogeneity. Crucially, we expand the framework to incorporate emerging modalities (e.g., oxeiptosis, alkalipoptosis), offering a dynamic extension to the static model. We systematically dissect their signaling networks, regulatory logic, and therapeutic strategies in both oncological and non-oncological settings. For the first time, we propose a translational research roadmap that identifies key bottlenecks across these pathways—including biomarker scarcity, systemic toxicity, and mechanistic heterogeneity—and prioritizes solutions tailored to each. Unlike existing reviews, our metabolic vulnerability atlas enables patient stratification and guides the rational design of selective modulators, supported by a bidirectional feedback loop between bench and bedside. By redefining metabolic cell death as a sabotage mechanism rather than an apoptotic process, this framework challenges the apoptosis-centric paradigm and provides a robust theoretical foundation for next-generation precision therapies that directly target the metabolic determinants of cell fate. These concepts are illustrated in an integrated schematic (Fig. 1), which sets the stage for the mechanistic and therapeutic analyses that follow.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700693","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":"Genome-wide CRISPR screen reveals CGS-15943 induced heme-dependent cell death mediated by aryl hydrocarbon receptor in lung cancer cells","authors":"Bach D. Nguyen,&nbsp;Siva K. Kolluri","doi":"10.1007/s10495-026-02410-2","DOIUrl":"10.1007/s10495-026-02410-2","url":null,"abstract":"<div><p>Induction of programmed cancer cell death by selective aryl hydrocarbon receptor (AHR) ligands represents a promising strategy for developing novel anticancer therapeutics. In this study, we characterized the anticancer activity and underlying mechanism of the selective AHR ligand CGS-15943 in lung cancer cells. CGS-15943 potently inhibited the growth of lung cancer cell lines expressing high levels of AHR, whereas CRISPR-mediated knockout of AHR in H460 and H69AR cells markedly rescued cells from CGS-15943-induced cell death, demonstrating an essential role for AHR. To identify additional mediators of this response, we performed a genome-wide CRISPR knockout screen, which revealed eight enzymes involved in the heme biosynthesis pathway, three heme-containing enzymes, as well as AHR and its transcriptional partner ARNT, as critical determinants of CGS-15943-induced cell death. Transcriptomic analyses further showed that CGS-15943 induced AHR-dependent transcriptional programs enriched for oxidative stress and oxidized phospholipid response pathways. Together, these findings identify key components of the AHR signaling network that regulate a programmed heme-dependent cell death pathway and establish CGS-15943 as a promising lead compound for targeting AHR-positive lung cancers.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700610","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}