ACOT2 (acyl-CoA thioesterase 2) is a mitochondrial enzyme that catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A, with preferential activity toward long-chain acyl-CoAs (C14–C20). This catalytic activity regulates intracellular lipid levels and supports hepatic fatty acid oxidation. Beyond its classical thioesterase function, recent evidence suggests ACOT2 also exhibits serine protease activity against viral polyproteins 1. In acute myeloid leukemia (AML), ACOT2 is highly expressed and associated with poor overall survival and abnormal lipid metabolism, implicating dysregulated fatty acid synthesis and elongation pathways 2. ACOT2 expression also correlates with pancreatic adenocarcinoma susceptibility 3. During dengue virus infection, mitochondrial ACOT2 knockdown suppresses viral protein translation, genome replication, and infectious particle release 4, while separately ACOT2 contributes to dengue proliferation through its proteolytic activity on viral substrates 1. In metabolic disease, reduced ACOT2 expression in mice lacking acyloxyacyl hydrolase correlates with increased hepatic lipid accumulation and decreased fatty acid oxidation 5. These findings position ACOT2 as a pivotal regulator linking lipid metabolism to cancer progression and viral pathogenesis, with potential therapeutic implications in AML and infectious disease.