Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism

Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUH K109R -mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo . In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUH K109R -mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.