ACSS3 (acyl-CoA synthetase short chain family member 3) is a mitochondrial matrix enzyme that catalyzes the synthesis of acetyl-CoA from short-chain fatty acids, with propionate as its preferred substrate 1. The enzyme exhibits high affinity for propionic acid (KM = 0.19 mM) and can also utilize acetate and butyrate with lower efficiency 1. ACSS3 functions as a key metabolic regulator involved in lipid metabolism and cellular energy homeostasis. The enzyme participates in metabolic reprogramming by modulating fatty acid oxidation through CPT1A regulation and enhancing glycolysis 2. ACSS3 expression is regulated by fasting conditions, with levels significantly increased during ketogenic states 1. In disease contexts, ACSS3 demonstrates tumor suppressor properties in multiple cancers. It is downregulated in prostate cancer due to promoter methylation and inhibits cancer progression by reducing lipid droplet formation through PLIN3 destabilization 3. Similarly, ACSS3 suppresses non-small cell lung cancer by promoting p53-mediated ferroptosis 4. The enzyme also shows protective effects in idiopathic pulmonary fibrosis by maintaining metabolic homeostasis in epithelial cells 2. These findings establish ACSS3 as both a metabolic regulator and potential therapeutic target across various pathological conditions.