ACSF2 (acyl-CoA synthetase family member 2) catalyzes the initial step of fatty acid metabolism by forming thioesters with CoA, with preferential activity toward medium-chain substrates 1. The protein localizes to mitochondria and mitochondrial matrix, where it plays roles in both fatty acid oxidation and adipocyte differentiation 2. ACSF2 is transcriptionally regulated by HNF4 factors and is essential for intestinal stem cell renewal through fatty acid oxidation pathways 3. Beyond metabolic functions, ACSF2 has emerged as a critical mediator of renal pathology in diabetic nephropathy (DN). Lysine lactylation at the K182 site impairs ACSF2-mediated mitochondrial function, contributing to renal tubule injury 4. ACSF2 interacts with PGK1 to promote ferroptosis through Keap1/Nrf2 signaling dysregulation, driving DN progression 5. Additionally, ACSF2 participates in the Acsf2/PHB2/PINK1 mitophagy pathway; pharmacological activation of this pathway alleviates tubular injury 6. ACSF2 dysregulation extends to inflammatory and neoplastic diseases, with elevated expression identified in hepatocellular carcinoma and ulcerative colitis, correlating with ferroptosis pathways 78. These findings position ACSF2 as a multifunctional metabolic enzyme with pathogenic roles in metabolic, renal, inflammatory, and malignant diseases.