DLAT (dihydrolipoamide S-acetyltransferase) is the E2 catalytic component of the pyruvate dehydrogenase complex, catalyzing acetyl-CoA formation from pyruvate and thereby linking glycolysis to the tricarboxylic acid cycle 1. Beyond its canonical metabolic role, DLAT functions as a central regulator of cuproptosis, a copper-dependent form of cell death mediated by protein lipoylation 2. In hepatocellular carcinoma, DLAT exhibits unexpected acetyltransferase activity toward AUH (an enzyme in leucine catabolism), suppressing leucine degradation and sustaining mTOR activation—independent of its pyruvate dehydrogenase function 3. DLAT upregulation correlates with poor prognosis in HCC patients and promotes tumorigenesis by stabilizing mitochondrial function and reducing oxidative stress 4. Under hypoxic conditions, HIF-1α-mediated suppression of DLAT expression decreases copper-dependent cuproptosis sensitivity, enabling cancer progression 5. Conversely, DLAT expression in group-3 medulloblastomas primes cells for cuproptosis induction by elesclomol, a copper ionophore 1. These findings reveal DLAT as a metabolic node controlling both TCA cycle flux and cuproptosis susceptibility, with implications for cancer therapeutics targeting either leucine metabolism or copper-induced cell death pathways.