ACOT2 is a mitochondrial acyl-CoA thioesterase that catalyzes hydrolysis of acyl-CoAs into free fatty acids and coenzyme A, with preferential activity toward long-chain acyl-CoAs (C14-C20) 12. The enzyme contains an alpha/beta hydrolase fold with a catalytic triad (Ser294-His422-Asp388) 3, functioning as a regulator of intracellular fatty acid levels and hepatic fatty acid oxidation in mitochondria. Beyond its canonical lipase function, ACOT2 exhibits unexpected serine protease activity, cleaving dengue virus polyproteins to promote viral replication 4. Selective ACOT2 knockdown suppresses dengue serotype 2 replication, indicating its importance during viral infection 5. In hepatic metabolism, ACOT2 expression decreases in metabolic dysfunction-associated steatotic liver disease, and restoring ACOT2 levels may prevent fatty liver disease 6. Clinically, elevated ACOT2 expression in acute myeloid leukemia predicts poor overall survival and correlates with abnormal lipid metabolism 7. Genome-wide association studies identified ACOT2 as a pancreatic cancer susceptibility gene 8. ACOT2 also represents a gene regulatory hub in responses to endocrine-disrupting chemicals affecting cardiometabolic disease pathways 9, suggesting multiple therapeutic targeting opportunities.