Glucocorticoids elevate clear cell renal cell carcinoma sensitivity to HIF-2α inhibitors by suppressing H4K12 lactylation.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.