Metabolic Enzyme DLAT Hijacks Leucine Breakdown to Fuel Liver Cancer Growth

Cancer cells rewire their metabolism to sustain rapid growth, but the precise crosstalk between different metabolic pathways has remained poorly understood. This study sheds new light on how pyruvate metabolism and amino acid metabolism are linked in liver cancer — with significant implications for both oncology and metabolic health research.

The research team focused on DLAT (dihydrolipoamide S-acetyltransferase), a core component of the pyruvate dehydrogenase complex. While its canonical role is facilitating the conversion of pyruvate to acetyl-CoA, the team discovered it has a secondary, non-canonical function: acting as an acetyltransferase that modifies AUH, a key enzyme in leucine catabolism. By acetylating AUH at its K109 residue, DLAT inactivates it, causing leucine to accumulate inside hepatocellular carcinoma (HCC) cells.

This leucine accumulation is consequential. Leucine is a potent activator of mTORC1, the mammalian target of rapamycin complex 1, which drives cell growth and proliferation. By preventing leucine breakdown, DLAT effectively keeps mTOR in a constitutively active state, providing a sustained growth signal for tumor cells. Elevated DLAT expression in HCC patient tissue correlated with significantly worse prognosis, suggesting clinical relevance.

To therapeutically exploit this mechanism, the team designed an mRNA lipid nanoparticle (LNP) encoding an acetylation-resistant AUH mutant (AUHK109R). Delivering this construct restored leucine catabolism, suppressed mTOR activation, and inhibited tumor growth in mouse models — a striking proof-of-concept for mRNA-based metabolic cancer therapy.

This work is notable for revealing how a metabolic enzyme can acquire acetyltransferase activity to coordinate two major pathways. Caveats include reliance on preclinical models and availability of only the abstract for full methodological review.