Long-chain fatty acid-CoA ligase (ACSL) (ACSL)

Long-chain fatty acid-CoA ligase (ACSL) is a family of enzymes that catalyze the essential first step of fatty acid metabolism by converting free long-chain fatty acids (C12–C22) into fatty acyl-CoA esters (UniProt: P33121). This activation is required for fatty acids to participate in beta-oxidation for energy production or to be incorporated into complex lipids like triacylglycerols and phospholipids (PubMed: 21483018). In humans, the family consists of five isoforms (ACSL1, 3, 4, 5, and 6), each exhibiting unique tissue expression patterns and substrate affinities. ACSL4, in particular, has gained attention as a critical regulator of ferroptosis, a form of regulated cell death, and is frequently upregulated in aggressive cancers such as breast and hepatocellular carcinoma (PubMed: 28211521). ACSL1 and ACSL5 are heavily involved in metabolic homeostasis, with dysregulation linked to obesity, insulin resistance, and nonalcoholic fatty liver disease (PubMed: 24561266). While inhibitors like Triacsin C have been used in research to block ACSL activity, the development of isoform-specific drugs remains a primary therapeutic challenge to avoid broad metabolic side effects (PubMed: 17416344).

Other names

Long-chain fatty acyl-CoA synthetaseLACSFACLAcyl-CoA synthetase long-chain family memberFatty acid-CoA ligase, long chain

ACSL inhibitors block the ATP-dependent ligation of fatty acids with Coenzyme A, preventing the formation of fatty acyl-CoA and thereby inhibiting lipid-mediated signaling, membrane synthesis, and energy metabolism.