Acsl4, or acyl-CoA synthetase long-chain family member 4, is an enzyme that esterifies CoA into specific polyunsaturated fatty acids like arachidonic acid and adrenic acid [4]. It is an essential regulator in fatty acid (FA) metabolism, remodels cell membrane phospholipid composition, and balances eicosanoid biosynthesis. ACSL4 is also prominently involved in the ferroptosis pathway, a form of regulated necrotic cell death [4]. Genetic models, such as knockout mice, have been crucial in studying its functions.

In knockout mouse models, ACSL4 deficiency has been shown to confer protection against ferroptosis-mediated acute kidney injury. Cdh16Cre-ACSL4F/F mice with ACSL4 knockout in kidney tubules had reduced ferroptosis, inhibited functional and pathological injury, decreased inflammation, and macrophage infiltration [3]. In another study, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis, indicating ACSL4 as an essential component for ferroptosis execution [1]. Also, tumor ACSL4 deficiency accelerates tumor progression, suggesting its importance in tumor ferroptosis and immunity [2].

In conclusion, ACSL4 plays a vital role in ferroptosis and fatty acid metabolism. Model-based research, especially through KO/CKO mouse models, has revealed its significance in various disease conditions, including acute kidney injury, tumor progression, and ferroptosis-related diseases. Understanding ACSL4 provides potential therapeutic targets for these diseases.