HMGCL (3-hydroxy-3-methylglutaryl-CoA lyase) is a mitochondrial enzyme catalyzing the final step of ketogenesis, cleaving HMG-CoA into acetyl-CoA and acetoacetate to produce ketone bodies (β-hydroxybutyrate, acetoacetate) as alternative energy sources 1. It also functions in leucine catabolism 1. The enzyme requires metal cofactors including magnesium and manganese ions for activity. Beyond canonical ketogenesis, HMGCL regulates cellular metabolism through β-hydroxybutyrate (β-HB)-mediated epigenetic modifications. HMGCL increases histone H3K9 and H3K27 acetylation, modulating transcription of genes like DPP4 and FOXM1 23. Through β-HB production, HMGCL inhibits the PI3K/AKT/mTOR signaling pathway, promoting autophagy 4. Clinically, HMGCL deficiency causes hypoketotic hypoglycemia and coma 1, and has been identified as a causative gene in contiguous gene deletion syndromes affecting multiple loci 5. In cancer contexts, HMGCL expression is often reduced, promoting tumor progression through suppressed oxidative stress and ROS generation 67. Recent evidence suggests HMGCL may serve as a tumor suppressor, with therapeutic potential through metabolic modulation 23. HMGCL is also implicated as a potential MS susceptibility gene in brain tissue 8.