Cell Death and Differentiation最新文献

{"title":"Cancer-intrinsic Cxcl5 orchestrates a global metabolic reprogramming for resistance to oxidative cell death in 3D","authors":"Ramin Seo, Arvie Camille V. de Guzman, Sunghyouk Park, Ji Youn Lee, Suk-Jo Kang","doi":"10.1038/s41418-025-01466-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01466-y","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma is characterized by a three-dimensional (3D) tumor microenvironment devoid of oxygen and nutrients but enriched in extracellular matrix, which acts as a physical and chemical barrier. In 3D, cancer cells reprogram their metabolic pathways in ways that help them survive hostile conditions. However, little is known about the metabolic phenotypes of cancer cells in 3D and the intrinsic cues that modulate them. We found that <i>Cxcl5</i> deletion restricted pancreatic tumor growth in a 3D spheroid-in-Matrigel culture system without affecting cancer cell growth in 2D culture. <i>Cxcl5</i> deletion impaired 3D-specific global metabolic reprogramming, resistance to hypoxia-induced cell death, and upregulation of <i>Hif1α</i> and <i>Myc</i>. Overexpression of <i>Hif1α</i> and <i>Myc</i>, however, effectively restored 3D culture-induced metabolic reconfiguration, growth, redox homeostasis, and mitochondrial function in <i>Cxcl5</i>^−/− cells, reducing ferroptosis. We also found that pancreatic cancer patients with higher expression of hypoxia and metabolism-related genes whose expression is well-correlated with <i>CXCL5</i> generally have poorer prognosis. Together, our findings identify an unanticipated role of <i>Cxcl5</i> in orchestrating the cancer metabolic reprogramming in 3D culture that is required for energy and biomass maintenance and that restricts oxidative cell death. Thus, our results provide a rationale for targeting <i>CXCL5</i> as a promising therapeutic strategy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"122 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"c-Kit+ cells that intercalate with crypt Lgr5+ cells are distinctively multipotent in colonic epithelium renewal and repair","authors":"Qing Xu, Yuting Zeng, Lan Jiang, Yongjie Zhou, Zhenru Wu, Shiyu Liu, Ruoting Men, Shujun Li, Jiayin Yang, Wei Huang, Yujun Shi","doi":"10.1038/s41418-025-01471-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01471-1","url":null,"abstract":"<p>The colonic crypts are principally composed by Lgr5⁺ stem cells and deep crypt secretory (DCS) cells. c-Kit-expressing cells mark DCS cells and supply Wnt3, EGF, and Notch signals to support their neighboring crypt bottom-intermingled Lgr5⁺ cells. However, the role of c-Kit⁺ cells beyond supporting Lgr5⁺ cells in colonic epithelium remains unexplored. Here, we identify that c-Kit⁺ cells are a heterogeneous entity and possess stemness potency to differentiate into the entire spectrum of epithelial cells and renew the homeostatic colon. Intriguingly, c-Kit⁺ cells play a pivotal role in epithelium repair in mouse models of colitis when contemporary Lgr5⁺ cells are insufficient or absent. Depletion of c-Kit⁺ cells or inhibition of SCF/c-Kit signaling worsens, while supplementation of SCF alleviates colonic epithelium injury during colitis. Our findings unravel the fate and function of c-Kit⁺ cells in homeostatic colon and recovery during colonic epithelium injury which has translational implications for human inflammatory bowel diseases.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"3 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZNF451 collaborates with RNF8 to regulate RNF168 localization and amplify ubiquitination signaling to promote DNA damage repair and regulate radiosensitivity","authors":"Feng Xu, Qi Xia, Bin Chen, Ruru Wang, Jie Zhang, Xipeng Zhao, Zhaoyang Zhang, Zhicheng Yao, Jie Zhang, Shenglan Zhou, Xiaona Li, Biao Chen, An Xu, Lijun Wu, Guoping Zhao","doi":"10.1038/s41418-025-01472-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01472-0","url":null,"abstract":"<p>The ubiquitination of histone H2A/H2AX, catalyzed by RNF8/RNF168, is a crucial step in the repair of DNA double-strand breaks (DSBs), playing a significant role in transmitting and amplifying DNA damage response signals. However, the upstream regulatory mechanisms of RNF168 remain unclear. Here, we demonstrate that ZNF451 catalyzes the SUMOylation of RNF168, thereby regulating the ubiquitination of histone H2A/H2AX. Specifically, ZNF451 rapidly responds to radiation-induced DNA damage, accumulating abundantly at damage sites and catalyzing the SUMO2 modification of RNF168. This modification stabilizes RNF168, enhancing its accumulation at damage sites, which increases the ubiquitination levels of downstream histone H2A/H2AX and promotes the DNA damage repair process. Furthermore, we find that ZNF451 and RNF8 jointly regulate RNF168 in a novel manner, exhibiting both competitive and cooperative characteristics. The interaction between RNF168 and either ZNF451 or RNF8 mutually inhibits each other. However, simultaneous loss of ZNF451 and RNF8 markedly impedes the recruitment of RNF168 to damage sites. Whereas, varying expression levels of ZNF451 and RNF8 suggest that both facilitate the interaction between RNF168 and the downstream factor H2AX, but the interaction plateaus beyond a specific threshold. Altogether, these findings reveal that the SUMOylation catalyzed by ZNF451 is involved in regulating RNF168-induced ubiquitin signaling in DSBs repair and suggest that ZNF451 could serve as a potential therapeutic target in tumor radiotherapy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism","authors":"Qijie Zhao, Shisheng Zhou, Wenhui Lou, Hui Qian, Zhiwei Xu","doi":"10.1038/s41418-025-01473-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01473-z","url":null,"abstract":"<p>Cells produce metabolic intermediates through catalytic reactions, mainly via post-translational modifications. The modification of proteins by O-linked N-acetylglucosamine, known as O-GlcNAcylation, is one of the most common post-translational modifications. As O-GlcNAcylation and phosphorylation can occur at serine or threonine residues, it is crucial that the interplay between these two modifications is vital to bioenergetic and biosynthetic demand. Although emerging recognition linking O-GlcNAc modification and phosphorylation to protein functions has been obtained, the issue of how altered O-GlcNAcylation or phosphorylation regulates each other in the metabolic system remains uncertain. The combination of cell biological and proteomic approaches over the recent few years has not only highlighted the interactions between O-GlcNAcylation and phosphorylation in protein function but also prompted us to elucidate the underlying mechanisms behind this crosstalk controlling metabolic homeostasis. The purpose of this review is to summarize recent advances in the O-GlcNAcylation/phosphorylation regulation of the metabolic process. An extensive exploration of this interplay has significant implications for metabolic control systems, including glucose, lipid, and nucleotide metabolism, where dysregulation in O-GlcNAcylation and phosphorylation of metabolic syndrome is essential.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"30 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KDM3A controls postnatal hippocampal neurogenesis via dual regulation of the Wnt/β-catenin signaling pathway","authors":"Kin Pong U, Lin Gao, Huan Zhang, Zeyuan Ji, Jiacheng Lin, Shenyi Peng, Xiaohu Zhang, Shaolong Xue, Weifeng Qin, Lai Ling Tsang, Yonglun Kong, Yin Xia, Patrick Ming-Kuen Tang, Tao Wang, Wayne Yuk Wai Lee, Gang Li, Xiaohua Jiang","doi":"10.1038/s41418-025-01470-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01470-2","url":null,"abstract":"<p>Hippocampal neurogenesis, the generation of new neurons in the dentate gyrus (DG) of mammalian hippocampus, is essential for cognitive and emotional processes. Despite advances in understanding the transcription factors and signaling pathways that regulate DG neurogenesis, the epigenetic mechanisms underlying the molecular changes necessary for granule neuron generation remain poorly understood. In this study, we investigate the role of the H3K9 demethylase KDM3A in postnatal neurogenesis in mouse DG. Using <i>Kdm3a</i>-tdTomato reporter mice, we demonstrate that KDM3A is predominantly expressed in neural stem/progenitor cells (NSPCs) during postnatal DG development. Conventional or conditional knockout (cKO) of <i>Kdm3a</i> in NSPCs hinders postnatal neurogenesis, compromising learning and memory abilities and impairing brain injury repair in mice. Loss of KDM3A in NSPCs suppresses proliferation and neuronal differentiation while promoting glial differentiation in vitro. KDM3A localizes both in the nucleus and cytoplasm of NSPCs and regulates the Wnt/β-catenin signaling pathway through dual mechanisms. Firstly, KDM3A modulates the transcription of Wnt targets and a set of neurogenesis-related genes through its histone demethylase activity. Secondly, in the cytoplasm, KDM3A interacts with casein kinase I alpha (CK1α), regulating its ubiquitination. Loss of KDM3A enhances CK1α stability, leading to increased phosphorylation and degradation of β-catenin. Finally, quercetin, a geroprotective small molecule, upregulates KDM3A protein expression and promotes adult hippocampal neurogenesis following brain injury. However, these effects are diminished in <i>Kdm3a</i> KO mice, indicating that quercetin primarily promotes hippocampal neurogenesis through the regulation of KDM3A. In conclusion, our study highlights KDM3A as a crucial regulator of postnatal hippocampal neurogenesis, influencing NSPC proliferation and differentiation via the Wnt/β-catenin signaling pathway. These findings have potential implications for the development of new therapeutic approaches for neurological disorders and injuries.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-1β drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling","authors":"Stefanie M. Bader, Lena Scherer, Jan Schaefer, James P. Cooney, Liana Mackiewicz, Merle Dayton, Smitha Rose Georgy, Kathryn C. Davidson, Cody C. Allison, Marco J. Herold, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger","doi":"10.1038/s41418-025-01459-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01459-x","url":null,"abstract":"<p>Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1β levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (<i>C1/11/12</i>^{<i>−/−</i>}). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1β, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1β, but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1β is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Trim32-DPEP2 axis is an inflammatory switch in macrophages during intestinal inflammation","authors":"Zhiyan Zhan, Huisheng Liang, Zhuoqi Zhao, Liya Pan, Jing Li, Yuyun Chen, Zhoulonglong Xie, Zhilong Yan, Ying Xiang, Wenxue Liu, Li Hong","doi":"10.1038/s41418-025-01468-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01468-w","url":null,"abstract":"<p>The mechanisms via which inflammatory macrophages mediate intestinal inflammation are not completely understood. Herein, using merged analysis of RNA sequencing and mass spectrometry-based quantitative proteomics, we detected differences between proteomic and transcriptomic data in activated macrophages. Dipeptidase-2 (DPEP2), a member of the DPEP family, was highly expressed and then downregulated sharply at the protein level but not at the mRNA level in macrophages in response to inflammatory stimulation. Suppression of DPEP2 not only enhanced macrophage-mediated intestinal inflammation in vivo but also promoted the transduction of inflammatory pathways in macrophages in vitro. Mechanistically, overexpressed DPEP2 inhibited the transduction of inflammatory signals by resisting MAK3K7 in inactivated macrophages, whereas DPEP2 degradation by activated Trim32 resulted in strong activation of NF-κB and p38 MAPK signaling via the release of MAK3K7 in proinflammatory macrophages during the development of intestinal inflammation. The Trim32-DPEP2 axis accumulates the potential energy of inflammation in macrophages. These results identify DPEP2 as a key regulator of macrophage-mediated intestinal inflammation. Thus, the Trim32-DPEP2 axis may be a potential therapeutic target for the treatment of intestinal inflammation.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"90 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression","authors":"Qimei Pan, Peng Luo, Yuntan Qiu, Kaishun Hu, Lehang Lin, Heyun Zhang, Dong Yin, Chunmeng Shi","doi":"10.1038/s41418-025-01465-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01465-z","url":null,"abstract":"<p>Numerous genes exhibit periodic oscillations in mRNA expression, essential for orderly cell division. Mitosis-related mRNAs fluctuate cyclically from the G2 to M phase, primarily regulated by transcription factors. However, the role of post-transcriptional regulation in this process remains unclear. Here, we demonstrated a decrease in mRNA levels of centromere protein F (<i>CENPF</i>) from the early to late G2 phase. SETDB1-PC4-UPF1 serves as a crucial post-transcriptional machinery, orchestrating the periodic degradation of <i>CENPF</i> mRNA, ensuring balanced CENP expression, proper spindle assembly, and successful mitosis. In early G2, newly synthesized <i>CENPF</i> mRNAs accumulate and bind to PC4, leading to SETDB1-mediated PC4 dimethylation at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of <i>CENPF</i> mRNAs, forming a regulatory loop for CENP homeostasis. Elevated PC4 dimethylation in hepatocellular carcinoma, coupled with increased sensitivity to taxanes upon its inhibition, suggests promising therapeutic avenues. These findings suggest a post-transcriptional quality control mechanism regulating cyclic mitotic mRNA fluctuations, providing comprehensive insights into cell cycle gene regulation dynamics.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop","authors":"Junjun Xiong, Xuhui Ge, Dishui Pan, Yufeng Zhu, Yitong Zhou, Yu Gao, Haofan Wang, Xiaokun Wang, Yao Gu, Wu Ye, Honglin Teng, Xuhui Zhou, Zheng Wang, Wei Liu, Weihua Cai","doi":"10.1038/s41418-025-01467-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01467-x","url":null,"abstract":"<p>Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal ferroptosis in vitro and expanded infiltration of CD68⁺ macrophages/microglia, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of <i>Uchl1</i> inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of <i>Uchl1</i> and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma","authors":"Daniel Delgado-Bellido, Antonio Chacon-Barrado, Joaquin Olmedo-Pelayo, Carmen Jordán Perez, Paula Gilabert-Prieto, Juan Díaz-Martin, Angel Garcia-Diaz, F. J. Oliver, Enrique de Álava","doi":"10.1038/s41418-025-01469-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01469-9","url":null,"abstract":"<p>Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and is where Vasculogenic Mimicry (VM) was first described. VM enables aggressive cancer cells to independently form blood networks, complicating treatment for patients exhibiting VM. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK), enhancing the Kaiso/β-catenin/TCF-4 complex associated with VE-Cadherin and thereby promoting VM. Recently, an allosteric HIF-2α inhibitor (Belzutifan) was FDA-approved for VHL-associated ccRCCs. In this research, we elucidate the primary causes of VM formation in UM patients with chromosome 3p loss and chromosome 8q gain, identifying VHL, BAP1, and FAK as important factors driving VM and worsening prognosis. These factors promote abnormal activation of HIF-2α and VE-Cadherin under basal hypoxic conditions, leading to VM formation. Cytoscan 750k experiments on the MUM 2B cell line reveal a loss of chromosome 3p, where the VHL, BAP1, and CTNNB1 genes are located, and a gain of chromosome 8q (FAK), whereas the MUM 2C cell line shows a gain of chromosome 3p. This provides an outstanding cross-sectional model from patient samples to established cell lines for VM studies. LC-MS experiments demonstrate that VE-Cad/ENG expression is related to FAK activity in UM cell lines. Finally, using a combination of Belzutifan (HIF-2α inhibitor) and FAK inhibitor (FAKi), we observed a significant reduction in UM xenografts. Our results lead us to propose combining Belzutifan and FAKi as a personalized treatment strategy for UM patients. This approach inhibits VM formation and counters the initial hypoxic conditions resulting from chromosome 3p loss and chromosome 8q gain in UM patients, instilling confidence in the potential of this treatment strategy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}