Cell Death Discovery最新文献

{"title":"Radiobiological characterisation of a 28 MeV proton beam delivered by the MC-40 cyclotron.","authors":"Maria Rita Fabbrizi, Jonathan R Hughes, Leah D Punshon, Laura Hawkins, Vasily Sorokin, Alice Ormrod, Emma Melia, Karthik Vaidya, Carlos P Rubbi, Ben Phoenix, Mark A Hill, Jason L Parsons","doi":"10.1038/s41420-025-02635-1","DOIUrl":"10.1038/s41420-025-02635-1","url":null,"abstract":"<p><p>Proton beam therapy (PBT) is a targeted radiotherapy treatment that can deliver the majority of the radiation dose to the tumour being treated via the Bragg peak. However, there is biological and clinical uncertainty of PBT due to the increases in linear energy transfer (LET) at and around the Bragg peak. Through radiobiological characterisation of a 28 MeV pristine proton beam at several positions relative to the Bragg peak, we demonstrate that there are decreases in survival of head and neck squamous cell carcinoma (HNSCC) and HeLa cells relative to increasing LET. Through monitoring DNA damage using γH2AX/53BP1/OGG1 foci via immunofluorescence microscopy and different versions of the comet assay, we show that increasing relative biological effectiveness (RBE) is directly associated with predominantly DNA single strand breaks that were more difficult to repair and persisted, in addition to a strong correlation with increases in the presence of more persistent complex DNA damage. Increasing frequencies of micronuclei as a marker of chromosomal damage were also observed as a function of LET. Our data demonstrate that increases in LET across the Bragg peak can create changes in the DNA damage spectrum that drive the radiobiological response.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"334"},"PeriodicalIF":6.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12280003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682043","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 the integrated stress response and loss of cFLIP_L under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.","authors":"Rocío Mora-Molina, F Javier Fernández-Farrán, Abelardo López-Rivas, Carmen Palacios","doi":"10.1038/s41420-025-02625-3","DOIUrl":"10.1038/s41420-025-02625-3","url":null,"abstract":"<p><p>Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIP_L), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"332"},"PeriodicalIF":6.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667276","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":"Role of S-palmitoylation in digestive system diseases.","authors":"Hanqing Li, Qiuxiang Yuan, Shuangshuang Wang, Tao Yu, Xingsi Qi","doi":"10.1038/s41420-025-02629-z","DOIUrl":"10.1038/s41420-025-02629-z","url":null,"abstract":"<p><p>Digestive system diseases, including liver diseases, gastrointestinal cancers, and inflammatory bowel diseases, pose major health challenges worldwide. These conditions are influenced by a range of key metabolic signaling pathways, many of which are regulated by palmitoylation. Palmitoylation is a type of lipid modification catalyzed by DHHC palmitoyl S-acyltransferases (DHHC-PTAs) and depalmitoylases, which play critical roles in modulating protein localization, stability, and signal transduction. Dysregulation of S-palmitoylation is closely associated with numerous diseases, including these of the digestive system, through multiple key processes such as immune responses, lipid metabolism, and cellular signaling. Decades of investigations have driven the development of a large body of inhibitors targeting zDHHCs and depalmitoylases, such as S-(2-acetamidoethyl) 2-bromohexadecanethioate (MY-D-4), Artemisinin and Lomitapide. This review provides a comprehensive summary of the role of palmitoylation in digestive system diseases, discusses its effect on disease mechanisms. By elucidating the regulatory functions of palmitoylation under these conditions, this review aimed to identify new strategies for the diagnosis and treatment of digestive system disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"331"},"PeriodicalIF":6.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667277","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 role of hydroxyindoles in protecting neuronal cultures from ferroptosis.","authors":"Md Jakaria, Jason R Cannon","doi":"10.1038/s41420-025-02608-4","DOIUrl":"10.1038/s41420-025-02608-4","url":null,"abstract":"<p><p>Hydroxyindoles are organic compounds characterized by a hydroxyl group attached to an indole ring. One notable example is 5-hydroxyindole, which can be found in humans, plants, and microorganisms. The structure of 5-hydroxyindole is integral to molecules such as melanin, serotonin and 5-hydroxyindoleacetic acid (a serotonin metabolite). Ferroptosis is a regulated form of cell death driven by uncontrolled phospholipid peroxidation, which has been linked to the pathogenesis of neurodegenerative diseases, including Alzheimer's and Parkinson's. The impact of hydroxyindoles on ferroptosis remains largely unexplored. This study tests the hypothesis that different hydroxyindoles can modulate ferroptosis in neuronal cultures through specific structure-activity relationships. We used various pathway-specific inducers, including erastin, RSL3, and FINO2, to induce ferroptosis. Cytotoxicity was evaluated using calcein AM, MTT (thiazolyl blue tetrazolium bromide), and LDH (lactate dehydrogenase) release assays. Glutathione levels were measured with the monochlorobimane assay, and intracellular ATP (adenosine triphosphate) levels were quantified using the ATP-Glo™ Bioluminometric cell viability assay. We also performed the ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assay to evaluate the radical-trapping antioxidant activity of the compounds. Our findings indicate that hydroxyindoles function as a class of ferroptosis inhibitors in cell cultures. Among the hydroxyindole analogs studied, 3-hydroxyindole emerged as the most potent inhibitor of ferroptosis in both HT-22 (mouse hippocampal neurons) and N27 (rat dopaminergic neurons) cell lines. In contrast, 5-hydroxyindole and its specific analogs, such as serotonin and 5-hydroxyindoleacetic acid, were found to be less effective in inhibiting ferroptosis in HT-22 cells. Further investigations into the underlying mechanisms revealed that hydroxyindoles inhibit ferroptosis through their intrinsic radical-trapping antioxidant activity. In conclusion, several hydroxyindole analogs, including 3-hydroxyindole, 6-hydroxyindole, and 7-hydroxyindole, have been identified as inhibitors of ferroptosis, highlighting their potential as therapeutic agents for conditions involving neuronal loss caused by ferroptosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"329"},"PeriodicalIF":6.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648688","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":"Bisphenol-A disrupts mitochondrial functionality leading to senescence and apoptosis in human amniotic mesenchymal stromal cells.","authors":"Sara Ficai, Andrea Papait, Marta Magatti, Alice Masserdotti, Michael Gasik, Antonietta Rosa Silini, Ornella Parolini","doi":"10.1038/s41420-025-02620-8","DOIUrl":"10.1038/s41420-025-02620-8","url":null,"abstract":"<p><p>In today's context, microplastic pollution has become an increasingly pressing issue not only for the environmental fallout but also for the assumed negative effects on human health. It is now well-established that microplastics (>1 mm in size) can enter the human body through ingestion, inhalation, dermal contact and also maternal-fetal transmission. Alarming were the recent findings of microplastics within the human term placenta. Among the degradation by-products of microplastics, Bisphenol-A (BPA) has emerged as a hazardous chemical, with potential toxicity at multisystemic level, particularly on the earliest stages of human development. Based on these findings, our study focuses on assessing the impact of BPA on properties and functions of mesenchymal stromal cells isolated from the amniotic membrane (hAMSC) of the human term placenta. The amniotic membrane surrounds the fetus, playing a fundamental protective role toward toxic chemicals and pollutants that the mother may encounter. Our research revealed how exposure to increasing concentrations of BPA compromise mitochondrial functionality in hAMSC, resulting in enhanced production of reactive oxygen species at mitochondrial level (mtROS). This, in turn, leads to the stabilization of p53, which triggers an increased expression of p21 and p27 encoding genes and an imbalance in the genetic expression of Bax and Bcl-2. Additionally, we observed upregulated expression of cytokines and chemokines associated with the senescence-associated secretory phenotype (SASP). The increased oxidative stress, which plays a central role in BPA-mediated toxicity, can trigger the activation of the senescence pathways, or culminate in cell death, due to the overwhelming stress conditions. Therefore, our results provide novel insights into the mechanism of action of BPA and elucidates its impact on the functionality of hAMSC. This underscores the pressing need to reconsider the use of BPA as a plastic additive, mitigating the potential adverse effects on babies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"327"},"PeriodicalIF":6.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648685","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":"Single-cell RNA sequencing reveals the effects of mental stress on mouse mammary tumors and the tumor microenvironment.","authors":"Pengfei Liu, Wenjing Ma, Tao Wang, Jinhui Lü, Weizhong Wang, Yixing Wang, Qifan Tang, Jing Di, Evelyne Bischof, Qian Zhao, Zuoren Yu","doi":"10.1038/s41420-025-02619-1","DOIUrl":"10.1038/s41420-025-02619-1","url":null,"abstract":"<p><p>Mental stress has been shown to negatively impact the development and progression of human cancer, including breast cancer. However, its effects on the tumor microenvironment (TME) remain unclear. In this study, we applied single-cell sequencing analysis to tumor tissues from MMTV-PyMT transgenic mice with mammary gland tumors with or without exposure to mental stress. In association with a significant promotion of the cell cycle and tumor growth induced by mental stress, we observed the dedifferentiation of luminal subtype of tumor cells into a subgroup of cancer stem cell-like basal cells, as well as enhanced cell proliferation in epithelial tumor cells, endothelial cells, and fibroblasts. In addition, stress stimulation led to an increase in tumor-associated neutrophils (TANs) and tumor-infiltrating dendritic cells (TIDCs), while suppressing immune cells such as cytotoxic T lymphocytes (CTLs), naïve T cells, B cells, and NK cells within the TME. We also observed a shift in macrophages from the M1 to the M2 phenotype. Furthermore, pathway enrichment analysis of differentially expressed genes, gene signature U score analysis, and immunofluorescence staining of the tumor tissue sections were conducted for further validation. The current study not only systematically elucidates the impact of mental stress on mammary gland tumors and the TME in vivo, but also provides insights into the mechanism underlying mental stress-induced tumor growth and progression in breast cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"328"},"PeriodicalIF":6.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648686","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 EIF4EBP1 gene encoding 4EBP1 is transcriptionally upregulated by MYC and linked to shorter survival in medulloblastoma.","authors":"Laura Hruby, Katerina Schaal, Alberto Delaidelli, Daniel Picard, Christopher Dunham, Oksana Lewandowska, Tobias Reiff, Magalie Larcher, Celio Pouponnot, Poul Hb Sorensen, Barak Rotblat, Guido Reifenberger, Marc Remke, Gabriel Leprivier","doi":"10.1038/s41420-025-02601-x","DOIUrl":"10.1038/s41420-025-02601-x","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most common malignant brain tumor in childhood and is stratified into four molecular groups ‒ Wingless and Int-1 (WNT), Sonic hedgehog (SHH), Group 3 and Group 4. Group 3 MB patients exhibit the poorest prognosis, with a 5-year overall survival of <60%, followed by Group 4 MB patients. Apart from MYC amplification in a subset of Group 3 MBs, the molecular pathomechanisms driving aggressiveness of these tumors remain incompletely characterized. The gene encoding the mTOR substrate and mRNA translation inhibitor eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) represents a possible MYC target gene whose corresponding protein, 4EBP1, was shown to be more active in Group 3 versus Group 4 MBs. However, the prognostic role of 4EBP1 in MB and the mechanisms supporting 4EBP1 overexpression in Group 3 MB are still elusive. We analyzed EIF4EBP1 mRNA expression in publicly available data sets and found an upregulation in MB as compared to non-neoblastic brain. EIF4EBP1 mRNA expression levels were higher in Group 3 compared to Group 4 MBs. EIF4EBP1 mRNA expression was correlated with MYC expression, most prominently in Group 3 MBs. Survival analyses highlighted that high EIF4EBP1 mRNA expression was associated with reduced overall and event-free survival across all MB patients and in Group 3/Group 4 MB patients. Immunohistochemical evaluation of 4EBP1 protein expression in MB tissues confirmed that high levels of 4EBP1 are associated with poor outcome. Functional analyses revealed that MYC directly regulates EIF4EBP1 promoter activity, providing a mechanism for increased EIF4EBP1 mRNA levels in Group 3 MBs. Finally, we observed that 4EBP1 may support colony formation of in vitro cultured MB cells. Our data highlight that transcriptional upregulation of EIF4EBP1 by MYC promotes in vitro tumorigenicity of MB cells and associates with shorter survival of MB patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"330"},"PeriodicalIF":6.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648687","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":"Epigenetic targeting of MECOM/KRAS axis by JIB-04 impairs tumorigenesis and cisplatin resistance in MECOM-amplified ovarian cancer.","authors":"Ibha Singh, Amarnath Karna, Anita Prajapati, Ujjawal Solanki, Archana Mukherjee, Sheetal Uppal, Pawan Malhotra, Manoj Kumar, Pallavi Agarwal","doi":"10.1038/s41420-025-02618-2","DOIUrl":"10.1038/s41420-025-02618-2","url":null,"abstract":"<p><p>Copy number gene amplification and associated overexpression of driver oncogenes are genetic events that contribute to cancer progression and drug resistance. MDS1 and EVI1 Complex locus (MECOM) gene is copy number amplified and overexpressed in aggressive epithelial ovarian cancers. The biological function and precise molecular mechanism of MECOM in the progression and drug resistance of ovarian cancer remain unclear. Here, we unravel MECOM as a regulator of KRAS and its downstream MAP Kinase signalling pathway, and also identify epigenetic inhibitor JIB-04 as a pharmacological agent targeting MECOM/KRAS axis. RNAi-mediated attenuation of MECOM in ovarian cancer cells harboring MECOM amplification reduced their proliferation, impaired colony formation, and impeded cellular migration. ChIP-qPCR analysis confirmed binding of MECOM to the KRAS promoter, suggesting direct regulation of the KRAS gene at the transcriptional level. Further, MECOM promoted cellular proliferation by regulating KRAS-mediated ERK/ZEB1 signalling cascade. The anti-tumorigenic effects due to MECOM loss were phenocopied by the treatment of ovarian cancer cells harboring MECOM amplification with JIB-04 epigenetic inhibitor targeting Jumonji domain histone demethylase enzymes. By ChIP-qPCR, we show that JIB-04 induced transcriptional changes of MECOM by altering H3K27me3 demethylation at its promoter region. We further report that ovarian cancer cells expressing high-MECOM levels exhibit cisplatin resistance, which could be effectively reversed upon pre-treatment with JIB-04. The therapeutic efficacy of JIB-04 was further demonstrated in mice bearing ovarian cancer cell xenografts, where JIB-04 slowed down the tumor growth in corroboration with diminishing MECOM expression. RNA-sequencing analysis identified potential cisplatin resistance gene, SUB1, being regulated by JIB-04-mediated modulation of MECOM expression. Altogether, these data suggest that epigenetic silencing of MECOM by JIB-04 mediated H3K27me3 modulation is an important mechanism in ovarian cancer and provide a new therapeutic target for the treatment of ovarian cancers harboring MECOM amplification.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"326"},"PeriodicalIF":6.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641932","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":"Fat-cartilage axis: the regulation of IL-6/Osteopontin signaling in osteoarthritis of mice.","authors":"Bing-Yang Dai, Zhong-Lian Huang, Ming-Gui Bao, Hong-Jiang Chen, Xiao-Hui Lu, Jun Hu","doi":"10.1038/s41420-025-02622-6","DOIUrl":"10.1038/s41420-025-02622-6","url":null,"abstract":"<p><p>The infrapatellar fat pad (IPFP) acts as a bioactive reservoir, secreting proinflammatory cytokines that orchestrate both local and systemic inflammatory cascades. Despite its emerging role in knee osteoarthritis (OA) pathophysiology, the molecular and cellular mechanisms driving IPFP-mediated disease progression remain a critical gap in mechanistic understanding. 12-week-old male C57BL/6 mice underwent either destabilization of the medial meniscus (DMM) surgery or Sham surgery. Here, we find that the extreme sensitivity of IPFP makes it prone to act as a reservoir of inflammatory factors, which may indiscriminately disrupt the stability of its surrounding tissues. We further ascertain the role of IL-6 in initializing fibrosis in IPFP at early stage of OA and modulating osteopontin (OPN) secretion that cascades cartilage deterioration. Notably, removal of the IPFP in DMM mice reverses the abnormal functions of the knee joint. Compromising the progress of fibrosis by intra-IPFP injection of siRNA Cd61 or inhibition of OPN expression can drastically ameliorate cartilage deterioration. Our findings elucidate a pivotal role for IL-6 in instigating fibrotic remodeling within the IPFP during early-stage OA, concurrently regulating OPN secretion to propagate cartilage matrix degradation. This study thus establishes a conceptual framework for therapeutic intervention by targeting the IL-6/OPN signaling axis in the IPFP during OA initiation, offering a promising strategy to disrupt disease progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"325"},"PeriodicalIF":6.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641933","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 accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction.","authors":"Cristina Gatto, Maria Rosaria Rusciano, Daniela Sorriento, Paola Di Pietro, Angela Carmelita Abate, Valeria Visco, Nicola Montone, Pasquale Mone, Daniele Di Napoli, Pierpaolo Chivasso, Vito Domenico Bruno, Vincenza Valerio, Paolo Poggio, Guido Iaccarino, Gaetano Santulli, Carmine Vecchione, Albino Carrizzo, Michele Ciccarelli","doi":"10.1038/s41420-025-02628-0","DOIUrl":"10.1038/s41420-025-02628-0","url":null,"abstract":"<p><p>Hypoxia, a condition characterized by a temporary lack of oxygen, causes mitochondrial damage, which in turn leads to endothelial dysfunction. G-protein-coupled receptor kinase 2 (GRK2) plays a key role in vascular homeostasis and remodeling, influencing endothelial function through various pathways. GRK2 moves within the cellular compartments and is linked to mitochondrial function and biogenesis, promoting ATP production and protecting against oxidative stress and cell death. The present study examined how mitochondrial GRK2 accumulation affects vascular reactivity and endothelial function in transient hypoxic conditions. Using a cloning strategy, we employed a small peptide (10aa) TAT-conjugated based on the pleckstrin homology domain of GRK2 to redirect GRK2 from the plasma membrane to the mitochondria. Mitochondrial accumulation of GRK2 increases vasodilatory responses in isolated swine artery segments, indicating potential therapeutic applications for cardiovascular disorders. Furthermore, in endothelial cells, GRK2 accumulation within mitochondria protects membrane potential, mitochondrial mass and prevents oxidative damage and cell death caused by transient hypoxia. Our findings show that GRK2 accumulation in mitochondria represents a potential therapeutic target to prevent transient hypoxia-induced damage.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"324"},"PeriodicalIF":6.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636314","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}