Nature metabolism · 2025
Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.
СтатьяНазвание и аннотация: Перевод в очереди
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Li Jiao, Huang Kaimeng, Thakur Meha, McBride Fiona, Sadagopan Ananthan, Gallant Daniel S, Khanna Prateek, Laimon Yasmin Nabil, Li Bingchen, Mohanna Razan, Ge Maolin, Weiss Cary N, Achom Mingkee, Xu Qingru, Matar Sayed, Lee Gwo-Shu Mary, Huang Kun, Gui Miao, Wu Chin-Lee, Cornejo Kristine M, Choueiri Toni K, Ryback Birgitta A, Signoretti Sabina, Bar-Peled Liron, Viswanathan Srinivas R
Аннотация
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.