Cell Death Discovery最新文献

{"title":"NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.","authors":"Jiakun Li, Jiawei Yan, Guowei Tu, Wenjiao Jiang, Yue Qiu, Ying Su, Changhong Miao, Zhe Luo, Tiffany Horng","doi":"10.1038/s41420-025-02461-5","DOIUrl":"10.1038/s41420-025-02461-5","url":null,"abstract":"<p><p>Ischemia reperfusion injury (IRI) is commonly seen in surgical procedures involving cardiopulmonary bypass and post-shock reperfusion. Sudden restoration of blood flow after a period of ischemia triggers a rapid accumulation of reactive oxygen species (ROS) and oxidative stress that promote pathological injury. Macrophage-derived inflammatory responses are also thought to contribute to such injury, but how ROS influences tissue macrophages and their elaboration of inflammatory cytokines in IRI remains poorly understood. In this study, we showed that macrophages mobilize mitochondrial adaptations during reoxygenation, including mitochondrial fission and ubiquitin proteasome system (UPS) flux. Furthermore, the transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) is rapidly induced during reoxygenation in response to rising levels of ROS. Induction of NRF1 upregulates ubiquitin proteasome system (UPS) and mitophagy pathways to mediate mitochondrial fusion/fission dynamics and dampen ROS production, allowing for alleviation of oxidative stress and the inflammatory response. Conversely, the absence of myeloid NRF1 leads to increased ROS, driving enhanced inflammation and kidney injury in a mouse model of IRI. We thus identify macrophage NRF1 as a master regulator of mitochondrial homeostasis, antioxidant defense, and inflammatory responses in IRI.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"236"},"PeriodicalIF":6.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076279","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":"USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma.","authors":"Zhiyuan Liu, Kuo Yu, Kaile Chen, Yi Zhang, Kexiang Dai, Liang Zhao, Peng Zhao","doi":"10.1038/s41420-025-02522-9","DOIUrl":"10.1038/s41420-025-02522-9","url":null,"abstract":"<p><p>Glioblastoma (GBM), the most common and aggressive primary brain tumour, is associated with poor prognosis, primarily due to its stem-like subpopulation, glioblastoma stem cells (GSCs). The deubiquitinase (DUB) family has attracted an increasing amount of attention due to its roles in GSC biology and tumour aggressiveness. In this study, we focused on ubiquitin-specific peptidase 18 (USP18), a member of the DUB family whose role in GBM is poorly understood. Through integrated bioinformatics analyses and experimental investigations using patient-derived samples, cell models, and animal models, we elucidated the role of USP18 in enhancing GSC stemness and promoting malignant behaviours. Our findings revealed that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis. Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains. Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"237"},"PeriodicalIF":6.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076281","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":"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/s41420-025-02514-9","DOIUrl":"10.1038/s41420-025-02514-9","url":null,"abstract":"<p><p>Gastric cancer (GC) is one of the most common malignancies with a poor prognosis. The development of novel biomarkers is of utmost importance to screen patients with GC. Molecular mechanism study of GC may provide a research basis for the development of targeted drugs. We identified tRF-29-79MP9P9NH525 (tRF-29) as a GC-associated tRNA-derived fragment (tRF). The specific hair-pin structure reverse primer and amplification primers were first designed and then applied for tRF-29 quantification. Receiver operator characteristic curve, Kaplan-Meier survival curve, and multivariate Cox analysis were applied to analyze the diagnostic and prognostic values of tRF-29 in GC. Ethynyl-2'-deoxyuridine, cell cloning, Transwell assay, and flow cytometry were used to detect the effects of tRF-29 on proliferation, migration, and cell cycle distribution of GC cells. Xenograft tumor formation in NOD-SCID mice was applied in determining tRF-29's effects on tumor growth. Fluorescence in situ hybridization, dual luciferase reporter assay, Western blot, immunohistochemistry, and RNA-binding protein immunoprecipitation were conducted to explore the molecular mechanism underlying tRF-29 regulating GC development. It was found that tissue tRF-29 showed effective diagnostic efficiency in GC and could discriminate different gastric mucosa. Besides, plasma tRF-29 improved GC diagnostic values of common tumor markers and had prognostic values in GC. tRF-29 was found to suppress proliferation and cell cycle progression. tRF-29 inhibited the growth of xenograft tumors. Mechanically, tRF-29 exerted Kinesin family member 14 (KIF14) mRNA destabilization by combining with argonaute 2 (Ago2) and regulated AKT/P27 pathway. In conclusion, tRF-29 inhibited GC progression by combining with Ago2 and regulated AKT/P27 pathway by silencing KIF14 expression. In normal cells, tRF-29, derived from tRNA-ValACC, targets the 3'UTR region of KIF14 mRNA by forming RNA silencing complex with Ago2. Reduced KIF14 results in less phospholation of AKT. Subsequently, the expression of P27 is increased, while the expression of MMP-2 is decreased. Finally, the cell cycle is arrested, and the cell proliferation is suppressed, as well as the metastasis is inhibited. In gastric cancer cells, due to the downregulated of tRF-29, the expression of KIF14 is increased, thus the cell proliferation and metastasis are promoted via AKT pathway.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"238"},"PeriodicalIF":6.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076276","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":"Gastrointestinal acute radiation syndrome: current knowledge and perspectives.","authors":"Michael L Freeman","doi":"10.1038/s41420-025-02525-6","DOIUrl":"https://doi.org/10.1038/s41420-025-02525-6","url":null,"abstract":"<p><p>Acute radiation gastrointestinal syndrome (GI-ARS) develops when the intestine is rapidly exposed to large doses of ionizing radiation. In humans, GI-ARS occurs at radiation doses of 6 Gy, with doses of ≥10 Gy typically resulting in death within 10 days. This condition can be caused by various factors, including war, terrorism, nuclear power plant accidents, and cancer therapy-associated adverse events. Developing effective approaches for treating GI-ARS requires a comprehensive understanding of the syndrome. This review summarizes the current body of literature that defines GI-ARS as a consequence of intestinal irradiation. It highlights the paradigm shift in understanding which intestinal stem cells contribute to homeostasis, the critical role of vascular injury in the development of GI-ARS, and recent advances in research on crypt-villus regeneration following radiation injury.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"235"},"PeriodicalIF":6.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076274","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":"O-GlcNAcylation of NONO regulates paraspeckle component assembly and contributes to colon cancer cell proliferation.","authors":"Yeolhoe Kim, Kyung-Tae Lee, Han Byeol Kim, Hyeryeon Jung, Jeong Yeon Ko, Tae Hyun Kweon, Hari Chandana Yadavalli, Junghwa Seo, Suena Ji, Yun Ju Kim, Donghyuk Shin, Seong Wook Yang, Myeong Min Lee, Jin Won Cho, Eugene C Yi, Jin-Wu Nam, Won Ho Yang","doi":"10.1038/s41420-025-02405-z","DOIUrl":"10.1038/s41420-025-02405-z","url":null,"abstract":"<p><p>Non-POU domain-containing octamer-binding protein (NONO) is a multifunctional member of the Drosophila behavior/human splicing (DBHS) protein family with DNA- and RNA-binding activity. NONO is highly expressed in various types of cancer, and excessive O-GlcNAcylation has also been implicated in tumorigenesis. Although recent studies revealed that NONO is O-GlcNAcylated and that this modification is involved in DNA damage repair, it remains unknown whether O-GlcNAcylation of NONO regulates cancer cell proliferation. Additionally, little is known about the effect of O-GlcNAcylation on other biological properties of NONO. In this study, we identify Thr440 as the primary NONO O-GlcNAcylation site and demonstrates its crucial role in the assembly of paraspeckles, an important subnuclear compartment that facilitates NONO-dependent transcriptional regulation in mammalian cells. Moreover, we found that O-GlcNAcylation of NONO is required to maintain the expression of genes related to microtubule cytoskeleton organization involved in mitosis and to suppress the expression of genes related to cellular response to type I interferon. Regarding the regulation of these genes, depletion of NONO O-GlcNAcylation at Thr440 significantly inhibited the proliferation of colon cancer cells. Collectively, our findings highlight NONO O-GlcNAcylation as a key regulator modulating paraspeckle formation and as a candidate therapeutic target in colon cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"234"},"PeriodicalIF":6.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973826","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":"Correction: Diazinon induces testicular dysfunction and testicular cell damage through increased reactive oxygen species production in mouse.","authors":"Ran Lee, Won-Young Lee, Dong-Wook Kim, Hyun-Jung Park","doi":"10.1038/s41420-025-02520-x","DOIUrl":"10.1038/s41420-025-02520-x","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"233"},"PeriodicalIF":6.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973211","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 ankyrin repeat-containing proteins in epigenetic and transcriptional regulation.","authors":"Meijuan Wu, Yulu Zhao, Jiahe Yang, Fangyuan Yang, Yeyang Dai, Qian Wang, Cheng Chen, Xiaoyuan Chu","doi":"10.1038/s41420-025-02519-4","DOIUrl":"10.1038/s41420-025-02519-4","url":null,"abstract":"<p><p>Ankyrin repeat (AR) motif is one of the most abundant repeat motifs found in eukaryotic proteins. It functions in mediating protein-protein interactions and regulating numerous biological functions. Interestingly, some AR-containing proteins are involved in epigenetic and transcriptional events. Our review aims to characterize the structure and post-translational modification of AR, summarize the prominent role of AR-containing proteins in epigenetic and transcriptional events, emphasizing the crucial functions mediated by AR motifs.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"232"},"PeriodicalIF":6.1,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986240","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":"Physiological roles and therapeutic implications of USP6.","authors":"Suaad Syed, Muhammad Yasir Khan Painda, Dawood Ghafoor, Dongjin Gu, Feng Wang","doi":"10.1038/s41420-025-02466-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02466-0","url":null,"abstract":"<p><p>Ubiquitin-specific protease 6 (USP6) is a member of deubiquitinating enzyme family, recognized for its essential roles in physiological and pathological processes. USP6 is initially identified as a hominoid-specific enzyme residing on chromosome 17p13. USP6 is involved in regulating cellular functions, signaling pathways, protein degradation, intracellular trafficking, tumorigenesis and immune responses. USP6 is pivotal in signaling pathways, including NF-κB, JAK-STAT, and Wnt, which are fundamental for maintaining cellular homeostasis and mediating stress responses. Dysregulation of USP6 has been implicated in a spectrum of diseases, including bone tumors, breast and colorectal cancers, cranial fasciitis, and neurological disorders such as memory dysfunction. Furthermore, USP6 is involved in emerging therapeutic strategies highlighting its implications for drug development. A number of potential small molecule inhibitors are known to be responsible for suppression of USP6, such as Momelotinib (CYT387), FT385, USP30 Inh-1, -2 and -3, 2,6-Diaminopyridine-3,5-bis(thiocyanate) (PR-619) and so on. This review explores the emerging role of USP6 as a key regulator of cellular signaling pathways, its involvement in disease progression, its physiological functions, and the inhibitors that effectively suppress USP6 activity in detail. The comprehensive study provides insight to enhance our understanding of biological importance and therapeutic interventions of USP6 in drug development.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"231"},"PeriodicalIF":6.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965629","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":"SUMO2/3 modification of transcription-associated proteins controls cell viability in response to oxygen and glucose deprivation-mediated stress.","authors":"Francisco Gallardo-Chamizo, Román González-Prieto, Vahid Jafari, Noelia Luna-Peláez, Alfred C O Vertegaal, Mario García-Domínguez","doi":"10.1038/s41420-025-02513-w","DOIUrl":"https://doi.org/10.1038/s41420-025-02513-w","url":null,"abstract":"<p><p>Because limited oxygen and glucose supply to tissues is a serious challenge that cells must properly measure to decide between surviving or triggering cell death, organisms have developed accurate mechanisms for sensing and signaling these conditions. In recent years, signaling through posttranslational modification of proteins by covalent attachment of the Small Ubiquitin-like Modifier (SUMO) is gaining notoriety. Enhanced sumoylation in response to oxygen and glucose deprivation (OGD) constitutes a safeguard mechanism for cells and a new avenue for therapeutic intervention. However, indiscriminate global sumoylation can limit the therapeutic potential that a more precise action on selected targets would have. To clear up this, we have conducted a proteomic approach in P19 cells to identify specific SUMO targets responding to OGD and to investigate the potential that these targets and their sumoylation have in preserving cells from death. Proteins undergoing sumoylation in response to OGD are mostly related to transcription and RNA processing, and the majority of them are rapidly desumoylated when restoring oxygen and glucose (ROG), confirming the high dynamics of this modification. Since OGD is linked to brain ischemia, we have also studied cells differentiated into neurons. However, no major differences have been observed between the SUMO-proteomes of proliferating and differentiated cells. We show that the overexpression of the transcription factor SOX2 or the SUMO ligase PIAS4 has a manifest cell protective effect largely depending on their sumoylation, and that maintaining the sumoylation capacity of the coregulator NAB2 is also important to face OGD. Conversely, sumoylation of the pluripotency factor OCT4, which is sumoylated under OGD, and is a target of the SUMO protease SENP7 for desumoylation after ROG, seems to block its cell survival-promoting capacity. Thus, better outcomes in cell protection would rely on the appropriate combination of sumoylated and non-sumoylated forms of selected factors.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"230"},"PeriodicalIF":6.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977076","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":"GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.","authors":"Jun-Dan Wang, Jin-Xing Wang, Zhi-Li Lin, Na Xu, Ling Zhang, Jia-Jun Liu, Rui Gao, Zi-Jie Long","doi":"10.1038/s41420-025-02502-z","DOIUrl":"https://doi.org/10.1038/s41420-025-02502-z","url":null,"abstract":"<p><p>Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T315I-induced resistance. Here, we reported that BCR/ABL-T315I mutant CML cells possessed a long-term proliferative capacity and tolerance to metabolic stress. Importantly, we also found that selenoamino acid metabolism was increased in the bone marrows of BCR/ABL-T315I patients compared with non-T315I patients by GSEA from RNA-Seq data. Indeed, GPX1 was highly expressed in T315I mutant cells, while knockout of GPX1 significantly suppressed cell proliferation and triggered apoptosis under glucose-deprived condition. GPX1 knockout showed decreased cell metabolism signaling as well as mitochondrial gene expression by RNA-Seq. Mechanistically, GPX1 maintained mitochondrial activity and oxygen consumption rate (OCR), retaining mitochondrial redox homeostasis and oxidative phosphorylation (OXPHOS). Additionally, mercaptosuccinic acid (MSA), a GPX inhibitor, inhibited CML colony formation and induced cell apoptosis under glucose-free condition. Therefore, GPX1 is a promising therapeutic target to overcome drug resistance induced by the T315I mutation, which provides a novel approach for BCR/ABL-T315I CML treatment by disturbing mitochondrial OXPHOS.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"229"},"PeriodicalIF":6.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967665","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}