Cell Death Discovery最新文献

{"title":"Empowering hypoxia to convert cold tumors into hot tumors for breast cancer immunotherapy.","authors":"Lu Liu, Danping Wu, Zhiwen Qian, Ying Jiang, Yilan You, YiDa Wang, Feng Zhang, Xin Ning, Jie Mei, Jabed Iqbal, Yanfang Gu, Yan Zhang","doi":"10.1038/s41420-025-02682-8","DOIUrl":"10.1038/s41420-025-02682-8","url":null,"abstract":"<p><p>Breast cancer remains the most common cancer among women globally and a leading cause of cancer-related death. Despite the promise of immunotherapy for triple-negative breast cancer (TNBC), its overall effectiveness is hindered by the cold tumor microenvironment (TME), characterized by sparse immune cell infiltration. This review explores the pivotal role of hypoxia in shaping the breast cancer TME and its influence on immunotherapy efficacy. As a defining feature of most solid tumors, including breast cancer, hypoxia drives aggressive tumor behavior, metastasis, and treatment resistance. The hypoxic TME promotes immune evasion and maintains the cold tumor phenotype. Targeting hypoxia offers a potential strategy for transforming cold breast tumors into hot tumors that respond more effectively to immunotherapy. This review consolidates existing insights into the interplay between hypoxia, tumor immunophenotypes, and immunotherapy in breast cancer. By analyzing the mechanisms through which hypoxia modulates the TME and immune response, it proposes innovative strategies to enhance immunotherapy outcomes. This comprehensive analysis lays the groundwork for developing more effective combination therapies to improve breast cancer prognosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"381"},"PeriodicalIF":7.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854716","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":"Comprehensive view on chemotherapy-free management of acute myeloid leukemia by using venetoclax in combination with targeted and/or immune therapies.","authors":"David Kegyes, Andrei Tat, Alin Stefan Vizitiu, Daiana Vazar-Tripon, Radu Ilie, Adrian Bogdan Tigu, Diana Cenariu, Anamaria Bancos, Sabina Iluta, Ciprian Jitaru, Madalina Nistor, Radu Tomai, Diana Gulei, Mihnea Zdrenghea, Hermann Einsele, Gabriel Ghiaur, Carlo M Croce, Ciprian Tomuleasa","doi":"10.1038/s41420-025-02678-4","DOIUrl":"10.1038/s41420-025-02678-4","url":null,"abstract":"<p><p>A hallmark of cancer biology is resistance to apoptosis. BCL-2 is an anti-apoptotic molecule that is being overexpressed in several myeloid diseases, such as acute myeloid leukemia and myelodysplastic syndromes, but also in several lymphoid cancers, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphomas and multiple myeloma. Venetoclax (VEN) is a BCL-2 small molecule inhibitor. Data about its structure, biochemical characteristics and in vitro efficacy against several blood cancer cell lines were first reported in 2013. Shortly after, the first clinical trials reported that single-agent VEN provides no long-term survival benefits. In contrast, when used in combination, VEN led to significantly improved outcomes and eventually to its first US FDA approvals in 2018. As the modern approach to treating hematological malignancies are the chemotherapy-free regimen, in the current manuscript, we provide a comprehensive view on all available therapies that are considered to be chemotherapy-free, with a special emphasis on acute myeloid leukemia (AML), where phase I-III clinical trials have provided the most data.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"379"},"PeriodicalIF":7.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12350645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844668","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":"AXL tyrosine kinase inhibitor TP-0903 induces ROS trigger neuroblastoma cell apoptosis via targeting the miR-335-3p/DKK1 expression.","authors":"Tsai-Yi Tseng, Shao-Hsuan Kao, Shun-Fa Yang, Yi-Chen Lin, Chu-Liang Lin, Juei-Liang Chen, Chien-Min Chen, Yi-Hsien Hsieh","doi":"10.1038/s41420-025-02681-9","DOIUrl":"10.1038/s41420-025-02681-9","url":null,"abstract":"<p><p>Neuroblastoma (NB) is an aggressive cancer and has poor prognosis in children. TP-0903, a multi-kinase inhibitor, shows inhibitory effects on NB but the mechanistic act is not completely explored. Here, we aimed to explore the anticancer activity of TP-0903 against NB cells and its underlying mechanism. In this study, our findings showed that TP-0903 ( ≥ 50 nM) significantly inhibited the growth of SH-SY5Y and Neuro-2a cells. Further results revealed that TP-0903 remarkably triggered cell apoptosis, mitochondrial membrane potential (MMP) lose, and caspase activation. Microarray assay, qRT-PCR, and Western blotting results indicated that DKK1 was downregulated by TP-0903. Notably, DKK1 is upregulated in NB tissues as comparing to normal tissues. Moreover, silencing DKK1 promoted TP-0903-induced apoptosis and caspase activation, and predicted the binding of TP-0903 to DKK1. In addition, we found that 3'-UTR of DKK1 had a potential target region for miR-335-3p and TP-0903 upregulated miR-335-3p expression. Of important, miR-335-3p mimic combined with TP-0903 provoked higher apoptosis and caspase activation than TP-0903 alone. We also observed that TP-0903 increased cellular reactive oxygen species (ROS), and inhibition of ROS reduced the apoptosis, PARP cleavage, and miR-335-3p, while increasing DKK1 in response to TP-0903. Finally, we demonstrated that TP-0903 significantly diminished the tumor growth and DKK1 expression in xenograft mice. Collectively, our findings indicate that TP-0903 triggers apoptotic cell death of NB cells, attributing to the ROS-mediated miR-335-3p upregulation and the consequent DKK1 downregulation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"378"},"PeriodicalIF":7.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12350951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844667","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":"Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy.","authors":"Yu-Na Hwang, Ju-Hee Park, Han-Heom Na, Tae-Hyung Kwon, Jin-Sung Park, Sehyun Chae, Young Taek Oh, Keun-Cheol Kim","doi":"10.1038/s41420-025-02674-8","DOIUrl":"10.1038/s41420-025-02674-8","url":null,"abstract":"<p><p>Cannabichromene (CBC: C₂₁H₃O₂, M.W.: 314.46 g) is a non-psychotropic phytocannabinoid derived from Cannabis sativa (hemp), and its potential therapeutic properties have attracted increasing attention. Specifically, it has demonstrated strong anti-inflammatory effects in animal models of edema through non-CB receptor mechanisms; however, further pharmacological studies based on cancer models are required. In this study, we investigated the molecular mechanisms underlying the anti-cancer activity of CBC in human pancreatic cancer cells. Through mRNA-seq analysis, the expression levels of many genes involved in cell death pathways were upregulated or downregulated after CBC treatment, and these included ferroptosis-related genes, such as HMOX1. We further confirmed the functional validity of apoptosis and ferroptosis induction after CBC treatment using various molecular assays. In addition, CBC preferentially increased the expression of TRPV1 and CB2. Accordingly, the effects on cell death were reversed after treatment with TRPV1 and CB2 inhibitors, suggesting that receptor expression is necessary for the induction of apoptotic cell death. Finally, we confirmed the consistent regulation of apoptosis, ferroptosis, and endocannabinoid receptors during tumor growth inhibition after CBC treatment using in vivo xenograft models. Therefore, we propose that CBC exhibits pharmacological activity via the integrative modulation of multiple cell death pathways, which can be exploited for pancreatic cancer therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"377"},"PeriodicalIF":7.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820682","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":"Long non-coding RNAs and autophagy: dual drivers of Hepatocellular carcinoma progression.","authors":"Himanshi Goyal, Jyotdeep Kaur","doi":"10.1038/s41420-025-02667-7","DOIUrl":"10.1038/s41420-025-02667-7","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is characterized by poor prognosis, high recurrence rates, and limited responsiveness to current therapies. Autophagy, a conserved catabolic pathway essential for cellular homeostasis, plays a paradoxical role in HCC, acting as a tumor suppressor during initiation but promoting survival and progression in advanced stages. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of autophagy, influencing tumorigenesis, metastasis, and therapy resistance through mechanisms such as miRNA sponging, chromatin remodeling, and protein interactions. This review describes how autophagy contributes to HCC at different stages, outlines the dual functions of lncRNAs as oncogenic drivers or tumor suppressors, and illustrates their integration into key signaling networks of autophagy (e.g., PI3K/AKT/mTOR, AMPK, Beclin-1). LncRNAs have been shown to modulate drug resistance, including resistance to first-line agents, by altering autophagic flux and associated molecular pathways. We also explored emerging strategies for targeting the lncRNA-autophagy axis, such as siRNAs, antisense oligonucleotides, and CRISPR/Cas systems, that have shown promise in preclinical studies and may be adapted for HCC. Furthermore, autophagy-related lncRNAs hold potential as non-invasive diagnostic and prognostic biomarkers and as predictors of recurrence. Integrating multi-omics approaches to validate these candidates will be critical for translation into clinical practice. Collectively, this review highlights the lncRNA-autophagy network as a promising frontier of biomarker discovery for precision diagnostics and targets for innovative therapeutics. The regulatory role of lncRNAs in autophagy presents a paradigm shift, heralding new strategies for targeted treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"376"},"PeriodicalIF":7.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12339970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820683","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":"Defective lipid droplet biogenesis exacerbates oleic acid-induced cellular homeostasis disruption and ferroptosis in mouse cardiac endothelial cells.","authors":"Yun-Ting Wang, Alexandra K Moura, Rui Zuo, Zhengchao Wang, Kiana Roudbari, Jenny Z Hu, Mi Wang, Pin-Lan Li, Yang Zhang, Xiang Li","doi":"10.1038/s41420-025-02669-5","DOIUrl":"10.1038/s41420-025-02669-5","url":null,"abstract":"<p><p>Endothelial dysfunction is a hallmark of various metabolic disorders and plays a pivotal role in the progression of cardiovascular diseases, including coronary microvascular dysfunction and myocardial ischemia. Lipid droplets (LDs) have emerged as key regulators of fatty acid metabolism in endothelial cells (ECs), but their functional role in lipotoxicity-induced EC damage in the context of coronary microvascular dysfunction remains unclear. Here, we examined the contribution of LD biogenesis to oleic acid-induced lipotoxic effects in mouse cardiac ECs (MCECs). Our findings reveal that oleic acid markedly increases LD biogenesis in MCECs via a diacylglycerol O-acyltransferase 1 (DGAT1)-dependent pathway. This process is accompanied by substantial disruptions in cellular homeostasis, including elevated endoplasmic reticulum (ER) stress, impaired mitochondrial respiration, reduced ATP production, and heightened hypoxic responses. Furthermore, oleic acid-induced lipotoxicity is primarily mediated by ferroptosis-a form of lipid peroxide-dependent, caspase-independent cell death. Notably, pharmacological inhibition or genetic knockdown of DGAT1, which diminishes LD biogenesis, exacerbates oleic acid-induced cellular stress, mitochondrial dysfunction, and ferroptosis in MCECs. These results suggest that LD biogenesis plays a protective role in mitigating lipotoxicity, preserving mitochondrial function, and preventing lipid peroxide accumulation and ferroptosis, thereby safeguarding cardiac microvascular endothelial function in the context of metabolic disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"374"},"PeriodicalIF":7.0,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811846","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":"Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions.","authors":"Xiuxiu Qiu, Ao Wang, Jiahui Wang, Zhanxia Zhang, Li Tao","doi":"10.1038/s41420-025-02670-y","DOIUrl":"10.1038/s41420-025-02670-y","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a leading cause of global cancer mortality, with therapeutic resistance constituting a major barrier to sustained clinical benefit. Mitochondrial metabolic reprogramming has emerged as a central adaptive mechanism that enables CRC cells to withstand hypoxia and therapeutic pressure, while concurrently driving resistance to chemotherapy, targeted agents, and immunotherapy. In this Review, we explore how mitochondrial metabolism contributes to therapeutic resistance, with particular emphasis on metabolic plasticity, redox balance, and organelle quality control. We also assess enabling technologies such as spatial transcriptomics, proteomics, and patient-derived organoids, and discuss their translational relevance in stratifying metabolic vulnerabilities and informing individualized therapies. Targeting mitochondrial rewiring represents a compelling strategy to overcome resistance and drive progress toward personalized CRC therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"375"},"PeriodicalIF":7.0,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811847","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":"Nicotinamide phosphoribosyltransferase in NAD⁺ metabolism: physiological and pathophysiological implications.","authors":"Weijia Zhang, Haoyu Ren, Wangwang Chen, Bo Hu, Chao Feng, Peishan Li, Yufang Shi, Jiankai Fang","doi":"10.1038/s41420-025-02672-w","DOIUrl":"10.1038/s41420-025-02672-w","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"371"},"PeriodicalIF":7.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798306","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":"Activation of APOBEC3 cytidine deaminases and endogenous retroviruses is integrated by MUC1-C in NSCLC cells.","authors":"Naoki Haratake, Shinkichi Takamori, Hideko Isozaki, Keisuke Shigeta, Chie Kikutake, Hiroki Ozawa, Atrayee Bhattacharya, Ayako Nakashoji, Mikita Suyama, Tomoyoshi Takenaka, Tomoharu Yoshizumi, Atsushi Osoegawa, Aaron N Hata, Donald Kufe","doi":"10.1038/s41420-025-02673-9","DOIUrl":"10.1038/s41420-025-02673-9","url":null,"abstract":"<p><p>The APOBEC3 (A3) genes encoding cytidine deaminases evolved in mammals to restrict retroviral replication. The MUC1 gene appeared in mammals to protect barrier tissues from viral infections. There is no known involvement of the MUC1 encoded MUC1-C/M1C protein in the regulation of A3s. We found that induction of MUC1-C in NSCLC cells treated with EGFR inhibitors integrates activation of an inflammatory memory response with the type I interferon (IFN) STAT1/STAT2/IRF9 (U-ISGF3) pathway. In turn, MUC1-C drives expression of A3 genes by activating their U-ISGF3-stimulated response elements (ISREs). We also report that MUC1-C-mediated induction of type II IFN STAT1 homodimer (U-GAF) complexes and the gamma-associated signaling (GAS) pathway drives human endogenous retrovirus HERV-K102/K108 expression. Our results in NSCLC cell line and patient-derived models further demonstrate that MUC1-C activates A3 and HERV-K expression by a common MUC1-C→STAT1 auto-inductive pathway. These previously unrecognized findings demonstrate that a MUC1-C-driven inflammatory pathway coordinates activation of APOBEC3 and HERV-K expression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"372"},"PeriodicalIF":7.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803696","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":"Astrocyte-derived CXCL10 exacerbates endothelial cells pyroptosis and blood-brain barrier disruption via CXCR3/cGAS/AIM2 pathway after intracerebral hemorrhage.","authors":"Wenqianjun Sheng, Zhangyi Wu, Jingyan Wei, Jun Wang, Shengfan Zhang, Zhiquan Ding, Jinhao Zhong, Dexian Deng, Zhenzhong Zhong, Yunong Yin, Yulong Li, Qinghua Wang","doi":"10.1038/s41420-025-02658-8","DOIUrl":"10.1038/s41420-025-02658-8","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a devastating disease that disrupts the blood-brain barrier (BBB), triggers inflammation, and leads to subsequent neurological deficits. Although the CXC chemokine receptor 3 (CXCR3) and its ligand CXCL10 are implicated in regulating inflammation, the specific role and mechanism of CXCR3 in ICH-induced BBB disruption remain unclear; furthermore, the involvement of the cGAS/AIM2 signaling pathway in endothelial pyroptosis after ICH needs further investigation. This study elucidates that activation of the CXCR3/CXCL10 axis exacerbates disruption of BBB integrity via the cGAS/AIM2 pathway following ICH. Utilizing a type IV collagenase-induced ICH model, we evaluated the therapeutic efficacy of the CXCR3 inhibitor AMG487. Results demonstrated that ICH induced the upregulation of CXCR3 and CXCL10, peaking at 24 h; immunofluorescence co-localization indicated CXCR3 was primarily localized to endothelial cells, while CXCL10 originated mainly from endothelial cells and astrocytes. AMG487 treatment improved neurological deficits and attenuated BBB disruption after ICH. Furthermore, exogenous CXCL10 activating CXCR3 upregulated the expression of cGAS/STING and pyroptosis-related proteins in vivo and vitro ICH models. However, inhibiting CXCR3 reversed the poor effects induced by CXCL10. Inhibition of the cGAS/AIM2 signaling pathway using A151 effectively reduced vascular endothelial pyroptosis and BBB disruption. In a co-culture model of endothelial cells and astrocytes, depleting CXCL10 downregulated the expression of cGAS, STING, AIM2, and pyroptosis-related proteins and alleviated endothelial pyroptosis. This study demonstrates that inhibition CXCR3 preserves BBB integrity and improves neurological deficits after ICH by suppressing endothelial pyroptosis via the cGAS/AIM2 signaling pathway. These findings provide novel insights into ICH pathogenesis, proposing CXCR3 as a potential target for BBB disruption and AMG487 as a promising therapeutic strategy for ICH patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"373"},"PeriodicalIF":7.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803697","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}