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

Abstract

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.

Melatonin alleviates ischemic stroke by inhibiting ferroptosis through the CYP1B1/ACSL4 pathway

“…The phospholipid in AA may be the main lipid peroxidation substrate for ferroptosis. 16 Current research has confirmed that CYP1B1 can affect the ubiquitination regulation of ACSL4 in the process of ferroptosis. 13 Additionally, reports have shown that high expression of CYP1B1 could improve brain injury.…”

“…Recent studies have indicated that ACSL4 catalyzes the conversion of arachidonic acid (AA) to arachidonoyl‐CoA, thereby promoting ferroptosis 16 . Exogenous AA enhances ferroptosis induced by RSL3.…”

“…ACSL4 tends to prefer AA as a substrate and catalyzes the formation of arachidonyl CoA from AA. The phospholipid in AA may be the main lipid peroxidation substrate for ferroptosis 16 …”

Portulaca oleracea L. polysaccharide inhibits ovarian cancer via inducing ACSL4-dependent ferroptosis

“…However, the weak carbon-hydrogen bonds between adjacent carbon-carbon double bonds of PUFA in membrane phospholipids can be oxidized by intracellular ROS via lipoxygenase to form lipid peroxides that induce ferroptosis [ 11 , 12 ]. Acyl coenzyme A synthase long chain family member 4 (ACSL4) is a regulator of lipid metabolism that mediates the insertion of PUFA into membrane phospholipids for remodeling [ 13 , 14 ]. Specifically, ACSL4 converts polyunsaturated fatty acids (PUFA), including arachidonic acid (AA) to AA-CoA, and then catalyzes AA-CoA to phosphatidylethanolamines (PEs) in the presence of lysophosphatidylcholine acyltransferase 3 (LPCAT3) [ 15 , 16 ].…”

Ferroptosis in chronic obstructive pulmonary disease: From cellular mechanisms to therapeutic applications

“…Pro-inflammatory macrophages with increased PRMT7 expression stimulate arachidonate 5-lipoxygenase and leukotriene B4 release, inducing acetyl coenzyme A (acyl-CoA) synthetase long-chain family member 4 (ACSL4) expression in BECs, rendering them more susceptible to ferroptosis in COPD. [ 1 , 10 ] Moreover, increased M2 macrophages and levels of matrix metalloproteinase (MMP) 9 and MMP12 were observed in CS-exposed mice and macrophages co-cultured with CSE-treated BECs. [ 11 ] CS exposure led to elevated NCOA4 levels and increased ferritin in BECs, resulting in iron overload and lipid peroxidation-induced ferroptosis.…”