Cell Death Discovery最新文献

{"title":"CCNE1 stabilizes ANLN by counteracting FZR1-mediated the ubiquitination modification to promotes triple negative breast cancer cell stemness and progression.","authors":"Sujuan Dai, Lin Li, Guangxiu Guo, Yun Peng, Huozhong Yuan, Juntao Li","doi":"10.1038/s41420-025-02518-5","DOIUrl":"https://doi.org/10.1038/s41420-025-02518-5","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies. In this study, we aimed to investigate the pivotal role of cyclin E1 (CCNE1) in the onset and progression of TNBC using comprehensive bioinformatic analysis and functional validation. We found significantly elevated CCNE1 expression in TNBC tissues compared to normal, which correlated with poor prognosis. Functional assessments in vitro and in vivo demonstrated that knockdown of CCNE1 impaired the proliferative, migratory, and invasive capacities of TNBC cells, promoted apoptosis, and reduced tumorigenicity. Furthermore, CCNE1 sustains the stem-like properties of TNBC cells and fuels malignant progression through Anillin (ANLN). Mechanistically, CCNE1 interacted with ANLN and stabilized its protein levels by counteracting Fizzy-related protein 1 (FZR1)-mediated the ubiquitination modification in TNBC. Mutation of the ubiquitination site in ANLN affected CCNE1's regulatory functions but not ANLN's intrinsic properties. Taken together, these findings underscore the role of CCNE1 in promoting TNBC cell stemness and progression via competitive inhibition of FZR1-mediated ANLN ubiquitination. Consequently, targeting CCNE1 emerges as a promising therapeutic approach for breast cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"228"},"PeriodicalIF":6.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964513","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 protective role of PYY in intestinal mucosal defects induced by SATB2 deficiency in inflammatory bowel disease.","authors":"Yao Liu, Lanqing Wu, Xiaoli Li, Yongyu Chen, Ruidong Chen, Caiyun Lv, Juan Chen, Xinjuan Fan, Guangxin Duan, Fan Zhong, Qi Sun, Qianyun Shi, Hengli Ni, Lina Sun, Jiaying Xu, Wen Tang, Jianming Li","doi":"10.1038/s41420-025-02511-y","DOIUrl":"https://doi.org/10.1038/s41420-025-02511-y","url":null,"abstract":"<p><p>Impaired colonic mucosal repair is a critical issue in inflammatory bowel diseases (IBD). SATB2 is essential for maintaining colonic epithelial homeostasis, but its role in mucosal repair is unclear. In this study, flow cytometry was used to assess SATB2's role in colonic epithelial repair in a radiation injury model. SATB2 knockout mice exhibited defective epithelial repair, with a marked reduction in goblet and enteroendocrine cells. Mechanistically, SATB2 directly regulated PPAR-γ transcription, and PYY was observed to translocate into the nucleus and promote the transcription of PPAR-γ target genes. In organoids derived from patients with Crohn's disease, PYY supplementation significantly improved epithelial regeneration, outperforming the PPAR-γ agonist rosiglitazone. In conclusion, SATB2 deficiency impairs colonic epithelial repair, which can be rescued by PYY through activation of PPAR-γ-dependent transcription. These findings suggest that PYY may serve as a promising therapeutic molecule to promote epithelial repair in IBD.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"227"},"PeriodicalIF":6.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977192","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":"MiR-125a-5p in MSC-derived small extracellular vesicles alleviates Müller cells injury in diabetic retinopathy by modulating mitophagy via PTP1B pathway.","authors":"Cong Liu, Jinjin Xiang, Yueqin Chen, Chang He, Jun Tong, Yinglin Liao, Huangyi Lei, Lingyun Sun, Genhong Yao, Zhenggao Xie","doi":"10.1038/s41420-025-02439-3","DOIUrl":"https://doi.org/10.1038/s41420-025-02439-3","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"226"},"PeriodicalIF":6.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985601","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 ANT2 in mitochondrial function and cancer cell survival: a target for therapeutic intervention.","authors":"Klara Bohacova, Zuzana Nahacka, Jana Dudova, Jaromira Kovarova, Jakub Rohlena, Michaela Rennerova, Barbora Judita Kasperova, Jan Stursa, Lukas Werner, Martin Haluzik, Jiri Neuzil, Sona Stemberkova Hubackova","doi":"10.1038/s41420-025-02510-z","DOIUrl":"https://doi.org/10.1038/s41420-025-02510-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"225"},"PeriodicalIF":6.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974435","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":"Extracellular vesicles derived from bone marrow mesenchymal stem cells regulate SREBF2/HMGB1 axis by transporting miR-378a-3p to inhibit ferroptosis in intestinal ischemia-reperfusion injury.","authors":"Zan Liu, Zitong Zhao, Zhenghui Xiao, Ming Li, Xiyang Wang, Yan Huang, Yong Li","doi":"10.1038/s41420-025-02509-6","DOIUrl":"https://doi.org/10.1038/s41420-025-02509-6","url":null,"abstract":"<p><p>Intestinal ischemia-reperfusion (II/R) injury represents a life-threatening and complex pathophysiological process that remains challenging to treat clinically, and emerging evidence suggests that ferroptosis plays an essential role in its pathogenesis. This study aimed to investigate whether extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) can mitigate II/R-induced ferroptosis in a murine model. Using a bioinformatics database, we initially identified genes with abnormal expression patterns in II/R injury. Then, we confirmed the association between II/R injury, ferroptosis, and the HMGB1/SREBF2 axis through in vivo and in vitro experiments. To determine the role of HMGB1 in hypoxia/reoxygenation (H/R)-induced ferroptosis in Caco-2 cells, we transfected cells with either sh-HMGB1 or control sh-NC constructs and developed an H/R model in vitro. Subsequently, we examined factors regulating HMGB1-mediated ferroptosis in Caco-2 cells and assessed the effect of BMSC-EVs on this process. To further explore the mechanism underlying the protective effects of BMSC-EVs in II/R injury, we screened for miRNAs with reduced expression during II/R and verified their involvement. Among these, miR-378a-3p was identified as a candidate for regulating ferroptosis. To confirm its functional role, we treated II/R mice with BMSC-EVs overexpressing miR-378a-3p and assessed the outcomes. Our findings revealed that HMGB1, which is a key regulatory factor of ferroptosis, was significantly upregulated during II/R injury, and its knockdown alleviated H/R-induced ferroptosis in Caco-2 cells. We also found that SREBF2 directly regulates HMGB1 expression to promote H/R-induced ferroptosis in vitro. Importantly, BMSC-EVs alleviated II/R injury by suppressing ferroptosis in Caco-2 cells, and mechanistically, miR-378a-3p, a miRNA derived from BMSC-EVs, inhibited II/R-induced ferroptosis by modulating the SREBF2/HMGB1 axis. In conclusion, BMSC-EVs may exert protective effects against II/R injury by delivering miR-378a-3p, which regulates the SREBF2/HMGB1 axis to suppress ferroptosis, providing important insights into the pathological mechanisms underlying II/R injury and potential therapeutic strategies for its management.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"223"},"PeriodicalIF":6.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959789","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":"Prognostic value of FLOT1-related gene signature in head and neck squamous cell carcinoma: insights into radioresistance mechanisms and clinical outcomes.","authors":"Min Kyeong Lee, Seon Rang Woo, Joo Kyung Noh, MinJi Bae, YeonSeo Lee, Soonki Min, Moonkyoo Kong, Young Chan Lee, Seong-Gyu Ko, Young-Gyu Eun","doi":"10.1038/s41420-025-02500-1","DOIUrl":"https://doi.org/10.1038/s41420-025-02500-1","url":null,"abstract":"<p><p>We aimed to develop and validate the ability of a FLOT1-related gene signature to predict survival in head and neck squamous cell carcinoma (HNSCC) patients and to explore FLOT1's role in modulating the responses to radiation therapy (RT). Using TCGA dataset, we identified a gene expression signature reflective of FLOT1 and applied LASSO regression to build a prediction model. Patients were stratified into high- and low-risk subgroups based on this signature. The prognostic value was confirmed across three independent cohorts, showing that high-risk patients had significantly poorer overall survival. Cox proportional hazards models were used to establish this gene signature as an independent prognostic factor for overall survival in HNSCC patients. Additionally, this signature predicted survival outcomes in patients undergoing RT. In vitro and in vivo experiments revealed that inhibiting FLOT1 expression increased the radiation sensitivity of HNSCC cells by modulating the phospho-PTEN/IGF1R axis. Moreover, silencing FLOT1 decreased radioresistance in radioresistant cell lines and xenograft mouse models. In conclusion, the FLOT1-related gene signature is a strong prognostic marker for HNSCC and may help identify patients who may benefit from RT.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"224"},"PeriodicalIF":6.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991311","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":"Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: a cutting-edge tool for advancing personalised treatments.","authors":"Qian Wang, Fangwei Yuan, Xianglin Zuo, Ming Li","doi":"10.1038/s41420-025-02505-w","DOIUrl":"https://doi.org/10.1038/s41420-025-02505-w","url":null,"abstract":"<p><p>Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"222"},"PeriodicalIF":6.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962878","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":"Obesity-associated reduction of miR-150-5p in extracellular vesicles promotes ventilator-induced lung injury by modulating the lysosomal degradation of VE-cadherin.","authors":"Yi Zhang, Changping Gu, Liang Zhao, Bailun Wang, Yongtao Sun, Yalin Lou, Daqing Ma, Yuelan Wang","doi":"10.1038/s41420-025-02499-5","DOIUrl":"https://doi.org/10.1038/s41420-025-02499-5","url":null,"abstract":"<p><p>Obese patient has a high risk of ventilator-induced lung injury (VILI) but its underlying mechanisms remain elusive. This study was designed to explore the role of circulating plasma extracellular vesicles (EVs) on the progression of VILI in the context of obesity. After high tidal volume mechanical ventilation, mice treated with plasma EVs from obese patients developed more severe lung damage than mice treated with plasma EVs from normal controls. miRNA sequencing of plasma EVs from obese patients revealed a significant downregulation of miR-150-5p compared to the others. miR-150-5p was found to target on XBP1s which subsequently regulated RAB7 as verified through dual-luciferase assays. This pathway promoted lysosomal degradation of vascular endothelial (VE)-cadherin, leading to an increased endothelial permeability. Obese mice showed an enhanced XBP1s/RAB7 expression, reduced VE-cadherin levels, and aggravated endothelial barrier damage and all of which intensified VILI. Administration of miR-150-5p agomir in obese mice mitigated VILI. Thus, this study highlights the low levels of miR-150-5p in EVs from obese patients modulated VILI severity via the XBP1s/RAB7 axis and the lysosomal degradation of VE-cadherin.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"220"},"PeriodicalIF":6.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978399","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":"Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application.","authors":"Na Liu, Tianqing Wu, Guohu Han, Minbin Chen","doi":"10.1038/s41420-025-02484-y","DOIUrl":"https://doi.org/10.1038/s41420-025-02484-y","url":null,"abstract":"<p><p>Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"221"},"PeriodicalIF":6.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960450","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 reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D.","authors":"Naijun Miao, Zhengchun Kang, Zhuning Wang, Wenyan Yu, Ting Liu, Ling-Zhijie Kong, Ying Zheng, Changli Ding, Zhiyong Zhang, Chen Zhong, Qingliang Fang, Kaichun Li","doi":"10.1038/s41420-025-02516-7","DOIUrl":"https://doi.org/10.1038/s41420-025-02516-7","url":null,"abstract":"<p><p>Although recent research has established that gasdermin D (GSDMD), a factor that drives pyroptosis, is essential for cell death and inflammation, its involvement in cancer metastasis has yet to be elucidated. In this study, GSDMD was significantly increased in lung neutrophils at the metastatic stage from a murine orthotropic 4T1 breast cancer model. Moreover, the N terminal domain from cleaved GSDMD exhibited a positive correlation with increased mitochondrial reactive oxygen species (mROS) and serum high mobility group box 1 (HMGB-1) levels. Mechanistically, mROS inhibition significantly suppressed GSDMD-N oligomerization and pore formation. In addition, the activation of GSDMD significantly enhanced the formation of neutrophil extracellular traps (NETs) following treatment with Cathepsin C. Within a murine orthotopic breast cancer model using 4T1 cell line, the inhibition of GSDMD through the application of LDC7559 significantly attenuated the metastatic spread of breast cancer to the lung. In addition, knockout of GSDMD reduced lung metastasis in E0771 intravenous injection murine model. Furthermore, inhibition of GSDMD reduced the number of myeloid derived suppressor cells (MDSC) in the metastatic lung of breast cancer mouse model, while concurrently increasing both the percentage and total cell count of CD8⁺ T cells, suggesting that mitochondrial dysfunction-dependent GSDMD activation promotes tumor microenvironment immunosuppression and NETs. GSDMD represents a promising therapeutic target for mitigating the metastatic progression of breast cancer to the lung.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"219"},"PeriodicalIF":6.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983281","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}