Cell Death & Disease最新文献_第9页

Non-catalytic role of SETD1A promotes gastric cancer cell proliferation through the E2F4-TAF6 axis in the cell cycle. SETD1A的非催化作用在细胞周期中通过E2F4-TAF6轴促进胃癌细胞增殖。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-23 DOI: 10.1038/s41419-025-07976-4

Meng Ning, Takayuki Hoshii, Takuya Nakagawa, Genki Usui, Shintaro Izumi, Kanako Hayashi, Makoto Matsumoto, Bahityar Rahmutulla, Masaki Fukuyo, Hiroyuki Abe, Tetsuo Ushiku, Atsushi Kaneda

{"title":"Non-catalytic role of SETD1A promotes gastric cancer cell proliferation through the E2F4-TAF6 axis in the cell cycle.","authors":"Meng Ning, Takayuki Hoshii, Takuya Nakagawa, Genki Usui, Shintaro Izumi, Kanako Hayashi, Makoto Matsumoto, Bahityar Rahmutulla, Masaki Fukuyo, Hiroyuki Abe, Tetsuo Ushiku, Atsushi Kaneda","doi":"10.1038/s41419-025-07976-4","DOIUrl":"https://doi.org/10.1038/s41419-025-07976-4","url":null,"abstract":"SETD1A is a member of the KMT2 histone H3K4 methyltransferase family of mammalian proteins. Aberrant SETD1A expression is associated with a poor prognosis in patients with gastric cancer (GC). We found that the catalytic domain of SETD1A is nonessential for GC cell proliferation, whereas the non-catalytic FLOS domain is essential. The loss of SETD1A commonly reduces the expression of E2F target genes in GC cell lines from the three independent molecular subtypes. A pooled CRISPR screen and cDNA rescue experiment showed that TAF6 acts downstream of SETD1A's non-catalytic function, which is essential for GC cell proliferation. Both SETD1A and TAF6 are required for G1/S cell cycle progression in GC cells. The mRNA expression of E2F4 highly correlated with both the SETD1A and TAF6 expression in patients with GC. Notably, E2F4 supported the expression of TAF6 but not that of SETD1A, suggesting that E2F4 serves as a coregulator of SETD1A, which is involved in regulating TAF6. These results demonstrate that the non-canonical roles of SETD1A and its downstream pathways are crucial for cell cycle progression in GC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"639"},"PeriodicalIF":9.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAD hijacks STING to impair antitumor immunity and radiotherapy efficacy of colorectal cancer. CAD劫持STING影响结直肠癌的抗肿瘤免疫和放疗效果。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-23 DOI: 10.1038/s41419-025-07964-8

Zhengkun Cai, Zeyuan Cheng, Lu Zhang, Yuhan Zhang, Jinming Shi, Jing Jin, Zeyun Mi, Zhiyong Yuan, Zhiqiang Wu

{"title":"CAD hijacks STING to impair antitumor immunity and radiotherapy efficacy of colorectal cancer.","authors":"Zhengkun Cai, Zeyuan Cheng, Lu Zhang, Yuhan Zhang, Jinming Shi, Jing Jin, Zeyun Mi, Zhiyong Yuan, Zhiqiang Wu","doi":"10.1038/s41419-025-07964-8","DOIUrl":"https://doi.org/10.1038/s41419-025-07964-8","url":null,"abstract":"Radiotherapy (RT)-elicited antitumor immunity serves as a pivotal mechanism in RT-mediated tumor control. The strategic integration of RT with immunotherapies, particularly immune checkpoint blockade (ICB), is revolutionizing cancer therapeutics, demonstrating remarkable clinical potential. In this context, identifying molecular targets to potentiate radioimmunotherapy (RIT) efficacy represents a critical research priority. Emerging as a central immunomodulatory axis, the cGAS/STING signaling pathway bridges DNA damage response with antitumor immunity, positioning itself as a prime therapeutic target for radiation sensitization. Our study unveils caspase-activated DNase (CAD) as a previously unrecognized suppressor of cGAS/STING signaling that governs radiosensitivity in colorectal cancer (CRC). CAD physically blocks STING dimerization and cGAMP binding through a nuclease-independent function, thereby compromising RT-induced STING activation and subsequent type I interferon (IFN-I) production. Functional analyses demonstrated that CAD ablation potentiates CD8+ T cell infiltration/activation within the tumor microenvironment and synergizes with anti-PD-1 immunotherapy upon radiation. Translational validation revealed clinical correlations between CAD overexpression in CRC specimens and suboptimal radiotherapy responses coupled with diminished intratumoral CD8+ T cell infiltration. Collectively, our findings establish CAD as a novel rheostat of cGAS-STING signaling and propose CAD inhibition as a promising combinatorial strategy to enhance RT and RIT efficacy in CRC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"641"},"PeriodicalIF":9.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NAD⁺ Metabolism-Mediated SURF4-STING Axis Enhances T-Cell Anti-Tumor Effects in the Ovarian Cancer Microenvironment. NAD+代谢介导的SURF4-STING轴增强卵巢癌微环境中t细胞抗肿瘤作用

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-23 DOI: 10.1038/s41419-025-07939-9

Jiacheng Shen, Fangfang Xu, Tingwei Liu, Yingjun Ye, Shaohua Xu

{"title":"NAD+ Metabolism-Mediated SURF4-STING Axis Enhances T-Cell Anti-Tumor Effects in the Ovarian Cancer Microenvironment.","authors":"Jiacheng Shen, Fangfang Xu, Tingwei Liu, Yingjun Ye, Shaohua Xu","doi":"10.1038/s41419-025-07939-9","DOIUrl":"https://doi.org/10.1038/s41419-025-07939-9","url":null,"abstract":"The anti-tumor function of T cells in the ovarian cancer (OC) microenvironment influences the prognosis of OC. Previous studies have indicated that metabolic competition among microenvironmental cells regulates the function of immune cells. Recent research has shown that NAD+ metabolism plays a significant role in modulating immune cell activity, and increasing NAD+ levels is a promising therapeutic strategy to enhance the effector functions of immune cells. However, the regulatory mechanisms of NAD+ metabolism on the anti-tumor function of T cells in the OC microenvironment remain unclear. This study found that exogenous supplementation of NAM to increase NAD+ levels in T cells significantly activates the endogenous p-STING axis and downstream interferon signaling within T cells, thereby enhancing T cell activation and anti-tumor effects. Concurrently, we discovered that elevated NAD+ levels promote the retention of STING on the Golgi apparatus. Mechanistically, we elucidated that the increase in NAD+ levels mediated by NAM downregulates the expression of SURF4 protein through ubiquitination and degradation, subsequently activating the p-STING axis in T cells. Furthermore, exogenous NAM supplementation can further enhance the activation of the T cell STING axis by PARP inhibitor (PARPi)-treated OC cells, and the combination of PARPi and NAM significantly augments the anti-tumor function of T cells, inhibiting the progression of OC. Our findings provide a molecular basis for the regulation of T cell anti-tumor function by NAD+, highlighting the potential strategy of targeting T cell metabolic reprogramming for the treatment of OC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"640"},"PeriodicalIF":9.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nucleolar proteomics identifies S100A16 as a key nucleolar protein driving breast cancer metastasis. 核仁蛋白质组学鉴定S100A16是驱动乳腺癌转移的关键核仁蛋白。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-22 DOI: 10.1038/s41419-025-07963-9

Brandon J Metge, Mohamed H Elbahoty, Amr R Elhamamsy, Anne E Popple, Bhavya Papineni, Rajeev S Samant, Lalita A Shevde

{"title":"Nucleolar proteomics identifies S100A16 as a key nucleolar protein driving breast cancer metastasis.","authors":"Brandon J Metge, Mohamed H Elbahoty, Amr R Elhamamsy, Anne E Popple, Bhavya Papineni, Rajeev S Samant, Lalita A Shevde","doi":"10.1038/s41419-025-07963-9","DOIUrl":"https://doi.org/10.1038/s41419-025-07963-9","url":null,"abstract":"Metastasis is the leading cause of poor clinical outcomes in solid tumors; yet despite recent advances many of the driving factors of metastasis remain poorly understood. Tumor cells that successfully metastasize are subject to numerous stress points from intrinsic and extrinsic factors that the cell must overcome to survive and colonize a secondary site. The nucleolus, the site of ribosome biogenesis, serves as a central hub for sensing and responding to cellular stress and plays a crucial role in this process; furthermore, emerging evidence highlights the potential role of ribosome biogenesis in driving metastasis. To further elucidate the interplay between nucleolar function and metastasis, we performed a comprehensive analysis of nucleolar proteomes from primary and metastatic breast cancer cell lines and identified proteins differentially enriched in the nucleoli of metastatic cells, of which 48 showed statistically significant enrichment. Among these, S100A16 was the most significantly enriched nucleolar protein. Notably, chromatin immunoprecipitation mass spectrometry (ChIP-MS) revealed that S100A16 was associated at rDNA loci with RPA194, the catalytic subunit of RNA Polymerase I, indicating a role in rRNA biosynthesis. Functionally, loss of S100A16 disrupted RNA Polymerase I activation and subsequent rRNA synthesis, reversed epithelial-to-mesenchymal transition, inhibited invasion, and reduced metastatic incidence in animal models of breast cancer. Clinically, elevated S100A16 expression correlated with enrichment of ribosome biogenesis pathways and reduced relapse-free survival in metastatic breast cancer patients. In summary, we identified a critical role for S100A16 as a molecular modulator in the nucleolus that impinges upon breast cancer metastasis.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"638"},"PeriodicalIF":9.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss of RhoA in microglia disables glycolytic adaptation and impairs spinal cord injury recovery through Arhgap25/HIF-1α pathway. 小胶质细胞中RhoA的缺失会通过Arhgap25/HIF-1α途径破坏糖酵解适应并损害脊髓损伤的恢复。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-22 DOI: 10.1038/s41419-025-07947-9

Jiale Cai, Xinya Zheng, Xiongbo Luo, Wenli Cui, Xinrui Ma, Shuyi Xu, Lanya Fu, Jiaqi Zhang, Yizhou Xu, Yunlun Li, Ye He, Xianghai Wang, Jiasong Guo

{"title":"Loss of RhoA in microglia disables glycolytic adaptation and impairs spinal cord injury recovery through Arhgap25/HIF-1α pathway.","authors":"Jiale Cai, Xinya Zheng, Xiongbo Luo, Wenli Cui, Xinrui Ma, Shuyi Xu, Lanya Fu, Jiaqi Zhang, Yizhou Xu, Yunlun Li, Ye He, Xianghai Wang, Jiasong Guo","doi":"10.1038/s41419-025-07947-9","DOIUrl":"https://doi.org/10.1038/s41419-025-07947-9","url":null,"abstract":"RhoA, a small GTPase, plays a pivotal role in various diseases, including spinal cord injury (SCI). Although RhoA inhibition has been traditionally viewed as beneficial for SCI repair, recent clinical trials of RhoA inhibitors in SCI have failed to show significant therapeutic efficacy, suggesting functional heterogeneity across different cell types. The role of RhoA in microglia, the key immune cells involve in SCI, remains poorly understood. Using microglial RhoA conditional knockout mice, this study demonstrated that RhoA deficiency in microglia attenuates the morphological and functional repair of the SCI mice, and impairs the microglial biofunctions of proliferation, phagocytosis, and migration. Single-cell RNA sequencing, bulk RNA sequencing, and metabolomics revealed that RhoA deficiency can attenuate the microglial glycolytic enzyme expression, ATP production, ECAR and OCR levels through the Arhgap25/HIF-1α pathway. Overall, this is the first study to demonstrate that microglial RhoA is essential for SCI repair, the Arhgap25/HIF-1α pathway mediated glucose metabolism might enlighten a novel insight to enrich the understanding on the complex roles of RhoA and microglia in SCI repair. Moreover, this study highlights the importance of considering cell-specific roles of RhoA in SCI repair and provides a foundation for developing targeted therapies aimed at microglial metabolic reprogramming. Schematic representation of the proposed mechanism by which microglial RhoA regulates glycolytic adaptation and spinal cord repair. (Created by Figdraw.com with permission of # wgq=r7c74c).","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"636"},"PeriodicalIF":9.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human iPSC-derived spinal neural progenitors enhance sensorimotor recovery in spinal cord-injured NOD-SCID mice via differentiation and microenvironment regulation. 人类ipsc衍生的脊髓神经祖细胞通过分化和微环境调节促进NOD-SCID脊髓损伤小鼠的感觉运动恢复。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-22 DOI: 10.1038/s41419-025-07961-x

Xuanbao Yao, Kehua Zhang, Tao Na, Yuchun Wang, Yuhan Guo, Jiajie Xi, Xiang Li, Shufang Meng, Miao Xu

{"title":"Human iPSC-derived spinal neural progenitors enhance sensorimotor recovery in spinal cord-injured NOD-SCID mice via differentiation and microenvironment regulation.","authors":"Xuanbao Yao, Kehua Zhang, Tao Na, Yuchun Wang, Yuhan Guo, Jiajie Xi, Xiang Li, Shufang Meng, Miao Xu","doi":"10.1038/s41419-025-07961-x","DOIUrl":"https://doi.org/10.1038/s41419-025-07961-x","url":null,"abstract":"Spinal cord injury (SCI) remains a significant clinical challenge and poses a dramatic threat to the life quality of patients due to limited neural regeneration and detrimental post-injury alternations in tissue microenvironment. We developed a therapeutic approach by transplanting spinal neural progenitor cells (spNPGs), derived from human induced pluripotent stem cell (iPSC)-generated neuromesodermal progenitors, into a contusive SCI model in NOD-SCID mice. Single-cell RNA sequencing mapped the in vitro differentiation of iPSC-spNPGs, confirming their specification into spinal neuronal lineages. Single-nucleus transcriptomics at 1 week post-transplantation showed that the grafted cells differentiated in vivo into motor neurons and two interneuron subtypes (V2 and dI4). Additionally, spNPGs integrated into host neural circuits, enhancing synaptic connectivity, while simultaneously modulating the injury microenvironment by shifting microglia and astrocyte polarization toward anti-inflammatory and neuroprotective phenotypes. This dual mechanism promoted axonal regrowth, remyelination, and significant sensorimotor recovery, as evidenced by improved locomotor scores. Our findings highlight the therapeutic potential of human iPSC-spNPGs in reconstructing neural networks and mitigating secondary damage, providing compelling preclinical evidence for advancing stem cell-based SCI therapies.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"637"},"PeriodicalIF":9.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10. 对比分析S100A10和S100A11在MASLD和肝癌发展中的作用，发现S100A10具有肿瘤抑制作用。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-21 DOI: 10.1038/s41419-025-07940-2

Etienne Delangre, Marta Correia de Sousa, Miranda Türkal, Monika Gjorgjieva, Suzanne Chartier, Grégoire Arnoux, Cyril Sobolewski, Margot Fournier, Christine Maeder, Laura Rubbia-Brandt, Pierre Maechler, Michelangelo Foti

{"title":"Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10.","authors":"Etienne Delangre, Marta Correia de Sousa, Miranda Türkal, Monika Gjorgjieva, Suzanne Chartier, Grégoire Arnoux, Cyril Sobolewski, Margot Fournier, Christine Maeder, Laura Rubbia-Brandt, Pierre Maechler, Michelangelo Foti","doi":"10.1038/s41419-025-07940-2","DOIUrl":"https://doi.org/10.1038/s41419-025-07940-2","url":null,"abstract":"S100 proteins are significantly deregulated in hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the impact of hepatocyte downregulation of two closely-related members of the S100 family, S100A10 and S100A11, in complementary mouse models of MASLD and liver cancer. Hepatotropic AAV8 encoding shRNAs targeting S100A10 or S100A11 were used to downregulate these proteins specifically in the liver of mice fed a diet inducing hepatic steatosis, inflammation, and fibrosis and in a genetic mouse model of MASLD bearing hepatocyte-specific deletion of PTEN (LPTENKO). The impact of S100A10 or S100A11 downregulation on liver tumor development was further investigated in aged LPTENKO mice spontaneously developing MASLD-driven HCC and in diethylnitrosamine (DEN)-injected mice fed or not with high fat diet. Finally, the upregulation and downregulations of S100A10 were performed in mice harbouring the over-expression of Myc and constitutively activated β-catenin, two main events occurring in a sub-type of human HCC. Downregulation of S100A10 promoted hepatocarcinogenesis in a fatty liver setting, while reducing steatosis and fibrosis development. S100A11 knock-down consistently reduced MASLD and tumoral growth. However, in vivo S100A11 downregulation triggered concomitant partial loss of endogenous protective S100A10. Overexpression of S100A10 reduced the volume of tumors and might represent a therapeutic option. The results show that both S100A10 and S100A11 play active roles in the development of MASLD. However, these two closely associated proteins present opposite contributions to hepatic cancer, S100A10 being protective and S100A11 deleterious.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"633"},"PeriodicalIF":9.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer. 纠正：CLDN6在乳腺癌中通过募集DLG1/PBK复合物触发nrf2介导的铁下垂。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-21 DOI: 10.1038/s41419-025-07910-8

Da Qi, Yan Lu, Huinan Qu, Yuan Dong, Qiu Jin, Minghao Sun, Chengshi Quan

引用次数: 0

MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6. MRPL13通过SLC25A6抑制mPTP开放，增强线粒体功能，促进卵巢癌肿瘤进展。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-21 DOI: 10.1038/s41419-025-07953-x

Ouxuan Liu, Yuexin Hu, Shuang Wang, Xin Nie, Yuxuan Wang, Xiangcheng Fan, Kai Zeng, Xiao Li, Bingying Liu, Bei Lin

{"title":"MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6.","authors":"Ouxuan Liu, Yuexin Hu, Shuang Wang, Xin Nie, Yuxuan Wang, Xiangcheng Fan, Kai Zeng, Xiao Li, Bingying Liu, Bei Lin","doi":"10.1038/s41419-025-07953-x","DOIUrl":"https://doi.org/10.1038/s41419-025-07953-x","url":null,"abstract":"Tumor cells typically exhibit dysregulation of mitochondrial energy metabolism and cell death. The role of mitochondrial function in ovarian cancer (OC) progression has garnered substantial attention, yet its precise molecular mechanisms remain elusive. Mitochondrial ribosomal protein L13 (MRPL13), involved in the translation of oxidative phosphorylation (OXPHOS) complex subunits, plays a critical role in regulating mitochondrial function. Our study demonstrated that MRPL13 is highly expressed in OC tissues and correlated with poor prognosis. Both in vitro and in vivo experiments confirmed that MRPL13 overexpression significantly promotes the malignant biological behavior of OC, while MRPL13 knockdown induces the opposite phenotype. Moreover, MRPL13 knockdown impairs mitochondrial function in OC cells, leading to decreased OXPHOS and ATP levels, increased reactive oxygen species (ROS) generation, mitochondrial depolarization, aberrant opening of the mitochondrial permeability transition pore (mPTP), and mitochondrial structural damage. Mechanistically, MRPL13 specifically interacts with SLC25A6 and facilitates its degradation via lysine (K)48-linked ubiquitination. MRPL13 inhibits mPTP opening by accelerating the degradation of SLC25A6, thereby preventing cytochrome c release into the cytoplasm, inhibiting cell death, and enhancing mitochondrial function. In conclusion, our study elucidates the mechanism by which the MRPL13-SLC25A6 axis enhances mitochondrial function and promotes tumor progression in OC by inhibiting mPTP opening, suggesting that MRPL13 holds significant potential for prognostic evaluation and targeted therapy in OC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"634"},"PeriodicalIF":9.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rewriting destiny-gene-hacked stem cells ignite a revolution against aging. 改写命运基因的干细胞点燃了一场对抗衰老的革命。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-08-21 DOI: 10.1038/s41419-025-07958-6

Liangyu Lin, Qun Xue, Gerry Melino, Yufang Shi

引用次数: 0