ACOT4 (acyl-CoA thioesterase 4) is a peroxisomal enzyme that catalyzes hydrolysis of acyl-CoA thioesters into free fatty acids and coenzyme A, regulating intracellular lipid levels 1. ACOT4 exhibits broad substrate specificity, functioning as a succinyl-CoA thioesterase while also hydrolyzing glutaryl-CoA and long-chain saturated acyl-CoAs 12. In humans, ACOT4 is the sole peroxisomal ACOT and functionally encompasses activities of multiple mouse peroxisomal thioesterases through convergent evolution 1. Mechanistically, ACOT4 regulation involves AKT-mediated phosphorylation at S392, which decreases binding to HSPA1A and promotes ACOT4 accumulation 3. The enzyme activates Akt/mTOR signaling pathways, protecting cells from calcium oxalate-induced apoptosis and injury 4. Clinically, ACOT4 expression is negatively correlated with pancreatic ductal carcinoma patient survival, with depletion attenuating tumor proliferation 3. ACOT4 represents part of a 10-gene fatty acid metabolism signature predictive of endometrial cancer prognosis 5. In inflammatory skin diseases, ACOT4 is differentially expressed in psoriatic sebaceous glands, contributing to disease-specific lipid metabolism alterations 6. These findings establish ACOT4 as both a metabolic regulator and potential therapeutic target across multiple disease contexts.