LDHA-driven ACAA2 lactylation at K270 reprograms fatty acid metabolism to promote clear cell renal cell carcinoma progression.

This study elucidates a novel lactate dehydrogenase A (LDHA)-acetyl CoA acyltransferase 2 (ACAA2)-lactylation axis driving clear cell renal cell carcinoma (ccRCC) progression through metabolic reprogramming. LDHA upregulation in ccRCC tissues is clinically linked to shorter overall patient survival. Functional assays demonstrated that LDHA overexpression enhances ccRCC proliferation, migration, and invasion, while knockdown attenuated these effects. Lactylome profiling identified 59 modified sites and revealed ACAA2 K270 lactylation (ACAA2-K270la) as a key regulator. Structural and biochemical analyses revealed K270 lactylation increases ACAA2 activity, promoting free fatty acids (FFAs) elevation. Exogenous FFAs recapitulated pro-tumorigenic effects in a dose-dependent manner. Mechanistically, LDHA-mediated ACAA2-K270la upregulated cyclins and cyclin-dependent kinases (CDKs), linking metabolic rewiring to cell cycle progression. These findings establish lactylation as a critical metabolic checkpoint in ccRCC, and reveal new therapeutic targets for metabolic intervention.