Metabolic and epigenetic reprogramming as novel vulnerabilities in renal cell carcinoma

Renal Cell Carcinomas (RCCs) are metabolically heterogeneous tumors with distinct genetic, epigenetic, and metabolic alterations. In clear cell Renal Cell Carcinoma, VHL gene loss leads to stabilization of Hypoxia Inducible Factors (HIF1α and HIF2α), promoting angiogenesis and metabolic reprogramming enhancing cellular energy production. Papillary Renal Cell Carcinoma, frequently harboring mutations in Tricarboxylic Acid cycle enzymes (FH, SDH), results in the accumulation of different “oncometabolites”, capable to drive pseudohypoxia and epigenetic dysregulation. Chromophobe Renal Cell Carcinoma is instead associated with mitochondrial defects and limited glycolytic activity. In this context, a tight interplay exists between metabolism and the epigenetic landscape. Oncometabolites are able to inhibit key chromatin-modifying enzymes, altering gene expression and promoting tumorigenesis. RCCs also exhibits frequent mutations in epigenetic regulators, further contributing to metabolic rewiring and tumor progression. Inhibiting oncometabolite accumulation, disrupting amino acid metabolism, modulating lipid anabolic routes, or targeting epigenetic enzymes could complement current treatments. Understanding the metabolic dependencies of RCC cells may lead to the development of novel, personalized therapies.