Cell Death Discovery最新文献

{"title":"Exercise-induced lactate suppresses ccRCC via CNDP2-mediated depletion of intracellular amino acids.","authors":"Rui Miao, Chunyan Liu, Yilong Wang, Hui Li, Cuihong Han, Chenchen Wang, Zhizhen Tian, Jiao Liu","doi":"10.1038/s41420-025-02609-3","DOIUrl":"https://doi.org/10.1038/s41420-025-02609-3","url":null,"abstract":"<p><p>Although epidemiological evidence has established a link between physical exercise and reduced risk and recurrence of multiple cancers, the association between physical exercise and cancer risk varies depending on the cancer site. Therefore, there is an urgent need to explore the molecular mechanisms underlying the antitumor effects of exercise to identify which types of cancers can benefit the most from physical exercise. Recent studies have shown that amino acids and exercise-induced lactate can be used by Carnosine Dipeptidase 2 (CNDP2) to synthesize lactoyl amino acids (Lac-AAs), which are then immediately secreted. Thus, we propose that lactate can deplete intracellular amino acids in a CNDP2-dependent manner, thereby exerting antitumor effects. Further bioinformatics analysis revealed that clear cell renal cell carcinoma (ccRCC) has the highest CNDP2 expression level among the 33 types of cancer tissues. Therefore, we focused on the inhibitory effects of lactate in this type of cancer and indeed confirmed its inhibitory roles in both cell and animal models. This study not only provides compelling evidence for the anti-cancer effects of physical exercise in ccRCC, but also provides novel insights into the biological role of lactate in the tumor microenvironment and offers potential therapeutic opportunities for mechanism-based treatment of ccRCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"356"},"PeriodicalIF":7.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752526","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":"P16-positive senescent cells promote DKD by the dysregulation of glycolysis and mitochondrial metabolism.","authors":"Xiao Lu, Jiao Wu, Ewud Agborbesong, Xiaogang Li","doi":"10.1038/s41420-025-02650-2","DOIUrl":"https://doi.org/10.1038/s41420-025-02650-2","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is characterized by kidney damage and abnormal renal energy metabolism, but the molecular mechanism of DKD is still unclear. In this study, we show that p16- positive senescent cells are an important regulator in the progression of DKD. The expression of p16 and senescence are increased in the kidneys of DM mice and DKD patients. To better understand the role of p16 in DKD, we induce type 1 diabetes in INK-ATTAC mice, a mouse model that allows the selective ablation of p16-expressing cells upon administration of the drug AP20187. We found that clearance of p16-positive cells, most of them are senescent cells, (1) decreased senescence and the expression of the components of the senescence-associated secretory phenotypes (SASPs), (2) restored kidney adenosine triphosphate (ATP) content, (3) decreased the expression of the key glycolytic genes to improve the metabolic reprogramming, (4) normalized the mitochondrial metabolism through AMPK and mTOR pathway, resulting in an amelioration of the progression of DKD. In addition, p16 mediated the blocking of the cell cycle is through the CDK4-Rb pathway in DKD kidneys. This study suggests that pharmacological deletion of p16-positive senescent cells may be a novel therapeutic strategy for DKD treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"355"},"PeriodicalIF":7.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752527","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":"Correction to: Identification of tRF-29-79MP9P9NH525 as a biomarker and tumor suppressor of gastric cancer via regulating KIF14/AKT pathway.","authors":"Jiaxin Ge, Ji Dai, Haoqiang Ji, Jie Guo, Xiaoban Shen, Desen Sun, Qiang Chen, Pan Chen, Guoliang Ye, Junming Guo, Shuangshuang Zhang","doi":"10.1038/s41420-025-02614-6","DOIUrl":"https://doi.org/10.1038/s41420-025-02614-6","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"353"},"PeriodicalIF":7.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752524","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":"Correction: CircRFWD3 promotes HNSCC metastasis by modulating miR-27a/b/PPARγ signaling.","authors":"Zihao Wei, Ying Wang, Jiakuan Peng, Honglin Li, Junjie Gu, Ning Ji, Taiwei Li, Xikun Zhou, Xin Zeng, Jing Li, Qianming Chen","doi":"10.1038/s41420-025-02547-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02547-0","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"354"},"PeriodicalIF":7.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752525","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":"A novel protein encoded by circUBE2G1 suppresses glycolysis in gastric cancer through binding to ENO1.","authors":"Lu Lu, Guoqing Guo, Jiahao Guo, Hanyang Li, Kexin Chen, Yuli Chen, Qiuhui Li, Qiunuo Li, Yuhao Diao, Ming Sun, Hao Wu, Xianghua Liu","doi":"10.1038/s41420-025-02644-0","DOIUrl":"10.1038/s41420-025-02644-0","url":null,"abstract":"<p><p>Gastric cancer (GC), a malignant neoplasm originating in the stomach epithelium, is characterized by substantial global incidence and mortality rates, posing a substantial threat to public health systems worldwide. The present study was designed to identify and validate a previously unannotated protein encoded by circular RNA (circRNA), with the principal objective of elucidating its functional significance and mechanistic basis in gastric carcinogenesis.CircUBE2G1 (hsa_circ_003239) was identified as a translationally active circRNA exhibiting significant downregulation in gastric cancer. The novel protein product derived from circUBE2G1 translation, designated circUBE2G1-99aa, was confirmed through co-immunoprecipitation coupled with tandem mass spectrometry (LC-MS/MS), representing the first documentation of its existence in human malignancies.CircUBE2G1-99aa exhibited marked downregulation in gastric cancer (GC), with its diminished expression levels demonstrating significant correlations with larger primary tumor size, lymph node metastasis, and advanced TNM stages. Functionally, circUBE2G1 exerted tumor-suppressive effects via its encoded protein circUBE2G1-99aa, not the full-length RNA, by inhibiting GC cell proliferation in vitro and in vivo. Mechanistically, circUBE2G1-99aa directly bound ENO1 and suppressed its glycolytic activity, thereby reducing glycolysis in GC cells. These findings delineate the functional and mechanistic landscape of circUBE2G1-99aa in gastric cancer, proposing its dual utility as both a prognostic biomarker and therapeutic target in clinical oncology.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"350"},"PeriodicalIF":7.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741315","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":"SPON2 facilitates osteosarcoma development by inducing M2 macrophage polarization through activation of the NF-κB/VEGF signaling axis.","authors":"Xinchang Lu, Xueping Zhang, Fengzhen Zhang, Wenhao Wang, Ruijie Liu, Yubao Hou, Weiye Shi, Jiazhen Li, Changliang Peng","doi":"10.1038/s41420-025-02626-2","DOIUrl":"10.1038/s41420-025-02626-2","url":null,"abstract":"<p><p>Osteosarcoma (OS) is an aggressive bone tumor with poor prognosis, particularly in metastatic cases. Here, we identify spondin 2 (SPON2) as a key driver of OS progression. SPON2 is significantly upregulated in OS tissues and cell lines and correlates with shorter patient survival. Functional assays show that SPON2 promotes OS cell proliferation, migration, invasion, and angiogenesis by enhancing the secretion of IL10, CCL2, and CSF1, which leads to M2 macrophage polarization and an immunosuppressive tumor microenvironment. In vitro, SPON2 knockdown reduces M2 macrophage markers and attenuates EMT phenotypes, as evidenced by decreased mesenchymal markers and preserved epithelial characteristics. Mechanistically, SPON2 activates the NF-κB/VEGF signaling axis to drive both macrophage polarization and EMT, thereby promoting tumor progression. In vivo, SPON2 knockdown in OS xenografts suppresses tumor growth, lung metastasis, and M2 polarization, while increasing M1-associated markers. Lipopolysaccharide (LPS) stimulation restores cytokine secretion and EMT marker expression in SPON2-knockdown models, suggesting that SPON2 acts through inflammation-responsive pathways. Together, these findings establish SPON2 as a key regulator of both immune modulation and metastatic behavior in OS, and highlight its potential as a therapeutic target.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"352"},"PeriodicalIF":7.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741318","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":"Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson's disease through inhibition of H3K4me3 demethylation.","authors":"Xiaoyuan Zhang, Fali Zhang, Yue Zeng, Aiying Li, Jiamao Yan, Pei Li, Kexin Qin, Teng Zhang, Jiaojiao Huang, Minghui Zhao, Massimo De Felici, Yang Zhou, Wei Shen","doi":"10.1038/s41420-025-02651-1","DOIUrl":"https://doi.org/10.1038/s41420-025-02651-1","url":null,"abstract":"<p><p>Parkinson's disease (PD), a neurodegenerative disorder caused by complex factors, is usually associated to mitochondrial dysfunctions but the links between such disorder and PD remain object of research. Here, we report that impaired mitochondrial quality control (MQC) system is a molecular basis of the mitochondrial dysfunction in PD and that tricarboxylic acid cycle (TCA cycle) disorder is the main feature of such mitochondrial dysfunction. Multi-omics analysis revealed that MDH2, OGDHL and IDH3G enzymes are bottlenecks in the enzymatic reactions of the TCA cycle in PD. Mechanistically, the abnormal α-KG/fumarate ratio caused by the TCA cycle bottleneck inhibits histone H3K4me3 demethylation and further enhances the expression of alpha-synuclein (SNCA), which may promote PD at an early stage. On these bases, we proposed a number of PD therapeutic strategies targeting mitochondria and histone methylation modifications, which proved to be effective in in vitro or in vivo models, especially citrate supplementation, in restoring normal TCA cycle enzymatic reactions. Taken together, our work highlights the non-negligible regulatory role of \"mitochondrial-nuclear\" communication in PD and provides important insights for the development of PD therapeutic strategies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"351"},"PeriodicalIF":7.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741317","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":"ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.","authors":"Mudassar Ali, Anjali, Koyeli Mapa","doi":"10.1038/s41420-025-02638-y","DOIUrl":"https://doi.org/10.1038/s41420-025-02638-y","url":null,"abstract":"<p><p>Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"349"},"PeriodicalIF":7.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741316","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":"FOXP2 suppresses gastric cancer progression by transcriptionally repressing FBXW2 via WASL degradation.","authors":"Sihan Lin, Wencheng Kong, Xinchun Liu, Guang Yin, Kangwen Cheng, Zonglei Mao, Yuqiang Shan, Xinger Lv","doi":"10.1038/s41420-025-02643-1","DOIUrl":"10.1038/s41420-025-02643-1","url":null,"abstract":"<p><p>Gastric cancer (GC) is an aggressive malignancy with poor clinical outcome. F-box and WD repeat domain-containing protein 2 (FBXW2), a substrate receptor of the SKP1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complex, has been implicated in tumor suppression across multiple malignancies; however, its role in GC progression remains undefined. Here, we integrated transcriptomic analyses using the TNMplot database and clinical specimens to demonstrate that FBXW2 expression was significantly downregulated in GC tissues, with low FBXW2 levels correlating closely with poor survival in GC patients. Functional characterization via gain- and loss-of-function strategies revealed that FBXW2 overexpression potently inhibited proliferation, cancer stem cell phenotype, migratory capacity, and invasive potential in human GC cell lines. Consistently, xenograft tumor models showed that FBXW2 overexpression delayed tumor growth and suppresses pulmonary metastasis. FBXW2 silencing promoted malignant progression both in vitro and in vivo. Label-free quantitative proteomics combined with mechanistic investigations identified WASP-like actin nucleation-promoting factor (WASL), a key regulator of cytoskeletal dynamics, as a direct downstream target of FBXW2. FBXW2 physically interacted with WASL and facilitated its ubiquitination-dependent proteasomal degradation. Ectopic WASL expression abrogated FBXW2-mediated suppression of GC cell viability and metastatic potential. Chromatin immunoprecipitation-PCR and DNA Pull Down analyses further revealed that Forkhead box P2 (FOXP2), a transcription factor frequently upregulated in GC, directly bound the FBXW2 promoter to repress its transcription, linking epigenetic dysregulation to FBXW2 downregulation in malignant tissues. Collectively, this study establishes FBXW2 as a critical tumor suppressor in GC, operating through ubiquitin-mediated degradation of WASL to inhibit cancer progression. Targeting the FOXP2-FBXW2-WASL axis may represent a promising therapeutic strategy for combating GC malignancy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"348"},"PeriodicalIF":7.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728304","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":"Development of a bispecific CDH17-GUCY2C ADC bearing the ferroptosis inducer RSL3 for the treatment of colorectal cancer.","authors":"Ying Zhang, Jing Du, Xiaohong Cui, Yuhang Ling, Chengwu Tang","doi":"10.1038/s41420-025-02652-0","DOIUrl":"10.1038/s41420-025-02652-0","url":null,"abstract":"<p><p>Colorectal cancer is a malignant tumor of the colon or rectum, with approximately 150,000 new cases each year. Current treatment strategies, such as surgery, chemotherapy, radiotherapy, and immunotherapy, face challenges ranging from cancer recurrence, drug resistance to significant toxicity. Therefore, these patients urgently need more effective treatments. Ferroptosis, a novel form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising new approach for treating colorectal cancer. Inactivation of phospholipid hydroperoxide glutathione peroxidase (GPX4) or the cysteine/glutamate antiporter SLC7A11 leads to the depletion of cellular glutathione (GSH), resulting in lipid peroxidation and subsequent ferroptosis. Here, we found that CDH17 and GUCY2C are co-overexpressed in colorectal cancer cells and developed a bispecific antibody-drug conjugate (BsADC) targeting CDH17 and GUCY2C, conjugated with the ferroptosis inducer RSL3 (a GPX4 inhibitor). Experimental results showed that, compared to monoclonal antibody ADCs, BsADC exhibits better binding and internalization activities, and could inhibit tumor cell proliferation more effectively. Moreover, the BsADC displayed an advantageous safety profile in mice. These findings suggest that the CDH17-GUCY2C BsADC, which induces ferroptosis in tumor cells, could be a promising new treatment for colorectal cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"347"},"PeriodicalIF":7.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728303","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}