ACOT12 (acyl-CoA thioesterase 12) is a cytosolic enzyme that catalyzes hydrolysis of acyl-CoAs into free fatty acids and coenzyme A, with preferential activity toward acetyl-CoA 1. This enzymatic function regulates intracellular lipid metabolism and acetyl-CoA levels, which serve as substrates for both energy production and epigenetic modifications through histone acetylation. Mechanistically, ACOT12 operates within the PPARα-mediated de novo lipogenesis pathway 2. The enzyme contains steroidogenic acute regulatory related lipid transfer domains, suggesting potential lipid-sensing and regulatory capacities beyond its catalytic function 3. ACOT12 expression is significantly downregulated in multiple disease states, including osteoarthritis, kidney fibrosis, and hepatocellular carcinoma. Clinically, ACOT12 suppression promotes cartilage degradation in osteoarthritis through acetyl-CoA accumulation and de novo lipogenesis stimulation 2, while ACOT12 deficiency exacerbates renal fibrosis through impaired pexophagy and lipid accumulation 4. In hepatocellular carcinoma, reduced ACOT12 expression correlates with poor prognosis and metastasis via epigenetic induction of epithelial-mesenchymal transition 5. Conversely, ACOT12 upregulation under energy stress converts acetyl-CoA to acetate, supporting brain metabolism and sustained ketogenesis 6. ACOT12 variations are associated with psoriasis susceptibility 7, and miR-155-5p-mediated ACOT12 suppression promotes glioma progression 8.