Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S. Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N. Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M. Cornejo, Toni K. Choueiri, Birgitta A. Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R. Viswanathan
{"title":"Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma","authors":"Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S. Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N. Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M. Cornejo, Toni K. Choueiri, Birgitta A. Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R. Viswanathan","doi":"10.1038/s42255-025-01218-9","DOIUrl":null,"url":null,"abstract":"<p>Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by <i>TFE3</i> gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including <i>EGLN1</i>, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"40 1","pages":""},"PeriodicalIF":18.9000,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s42255-025-01218-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma
Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.
期刊介绍：
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.
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