Acsl4, acyl-CoA synthetase long-chain family member 4, is an enzyme crucial for esterifying CoA into specific polyunsaturated fatty acids like arachidonic acid and adrenic acid. It is a key regulator in the ferroptosis pathway, which is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). ACSL4 also plays a significant role in fatty acid metabolism, remodeling cell-membrane phospholipid composition, regulating steroidogenesis, and balancing eicosanoid biosynthesis [3]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In ferroptosis-related studies, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis, indicating ACSL4 is an essential component for ferroptosis execution. ACSL4 enriches cellular membranes with long polyunsaturated ω6 fatty acids, dictating ferroptosis sensitivity [1]. In acute kidney injury (AKI), ACSL4 knockout in kidney tubules (Cdh16Cre-ACSL4F/F mice) significantly reduced ferroptosis, inhibited functional and pathological injury, decreased inflammation, and macrophage infiltration, suggesting ACSL4 is a potential target in AKI [2]. In ischemic stroke, knockdown of ACSL4 protected mice against brain ischemia, while overexpression exacerbated ischemic brain injury, with ACSL4 promoting neuronal death via enhancing lipid peroxidation and neuroinflammation [4].

In conclusion, ACSL4 is essential in ferroptosis and fatty acid metabolism. KO/CKO mouse models have revealed its role in diseases such as ferroptosis-related disorders, AKI, and ischemic stroke. These findings highlight ACSL4 as a potential therapeutic target in these disease areas.

References:

1. Doll, Sebastian, Proneth, Bettina, Tyurina, Yulia Y, Angeli, José Pedro Friedmann, Conrad, Marcus. 2016. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. In Nature chemical biology, 13, 91-98. doi:10.1038/nchembio.2239. https://pubmed.ncbi.nlm.nih.gov/27842070/

2. Wang, Yue, Zhang, Menghan, Bi, Ran, Cao, Qiuhua, Gao, Xinghua. 2022. ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury. In Redox biology, 51, 102262. doi:10.1016/j.redox.2022.102262. https://pubmed.ncbi.nlm.nih.gov/35180475/

3. Ding, Kaiyue, Liu, Chongbin, Li, Li, Luo, Shilu, Sun, Lin. 2023. Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism. In Chinese medical journal, 136, 2521-2537. doi:10.1097/CM9.0000000000002533. https://pubmed.ncbi.nlm.nih.gov/37442770/

4. Cui, Yu, Zhang, Yan, Zhao, Xiaolong, Xu, Rui, Zhang, Zhaolong. 2021. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. In Brain, behavior, and immunity, 93, 312-321. doi:10.1016/j.bbi.2021.01.003. https://pubmed.ncbi.nlm.nih.gov/33444733/