BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis

Metabolic dysregulation has been established as a key driver in tumorigenesis, but its underlying mechanisms in lung cancer remain poorly characterized. In this study, we performed nested case-control analyses in two prospective cohorts (208 and 144 matched pairs) to examine associations between plasma metabolites and lung cancer risk. Untargeted metabolomics identified circulating metabolites of the branched-chain amino acid (BCAA) pathway as significantly associated with lung cancer risk. An animal study demonstrated that a high-BCAA diet accelerated lung cancer progression in the Kras^G12D/+ mice model. Among the three BCAAs, leucine contributed much more to promoting lung cancer growth. Mechanistically, AUH-mediated acetyl-CoA production from leucine metabolism fuels cholesterol synthesis, promoting lipid raft formation and EGFR redistribution and activation, thereby driving lung tumorigenesis. Moreover, atorvastatin blocked leucine-induced tumor progression in mice. Overall, our findings provide experimental evidence that leucine-driven BCAA metabolic reprogramming promotes lung tumorigenesis via cholesterol metabolism, revealing a potential therapeutic target.