Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism

• Published in: Chinese medical journal Vol. 136; no. 21; pp. 2521 - 2537
• Main Authors: Ding, Kaiyue, Liu, Chongbin, Li, Li, Yang, Ming, Jiang, Na, Luo, Shilu, Sun, Lin
• Format: Journal Article
• Language: English
• Published: China Lippincott Williams & Wilkins 05.11.2023; Lippincott Williams & Wilkins Ovid Technologies; Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China%Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China; Wolters Kluwer
• Subjects: Adenosine; Cholesterol; Fatty acids; Ferroptosis; Hypoxia; Intellectual disabilities; Kinases; Lipids; Metabolism; MicroRNAs; Oxidation; Phosphatase; Polyunsaturated fatty acids; Proteins; Review; Ferroptosis; Metabolic diseases; Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4); Fatty acid metabolism; Ischemia/reperfusion; Cancer
• ISSN: 2542-5641; 0366-6999; 2542-5641
• DOI: 10.1097/CM9.0000000000002533

Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation. Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids; ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis, respectively. In addition, ACSL4 is an essential regulator of fatty acid (FA) metabolism. ACSL4 remodels the phospholipid composition of cell membranes, regulates steroidogenesis, and balances eicosanoid biosynthesis. In addition, ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology. Because it facilitates the cross-talk between ferroptosis and FA metabolism, ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries. In this review, we focus on the structure, biological function, and unique role of ASCL4 in various human diseases. Finally, we propose that ACSL4 might be a potential therapeutic target.