ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation

• Published in: Brain, behavior, and immunity Vol. 93; pp. 312 - 321
• Main Authors: Cui, Yu, Zhang, Yan, Zhao, Xiaolong, Shao, Liming, Liu, Guoping, Sun, Chengjian, Xu, Rui, Zhang, Zhaolong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.03.2021
• Subjects: ACSL4; Animals; Brain Injuries; Brain Ischemia; Coenzyme A Ligases - genetics; Ferroptosis; Ischemic Stroke; Mice; Neuroinflammation; Ferroptosis; Neuroinflammation; ACSL4; Ischemic stroke
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2021.01.003

•The expression of ACSL4 was decreased after ischemia which was mediated by HIF-1α.•Overexpression of ACSL4 exacerbated ischemic brain injury.•Knockdown of ACSL4 reduced ischemic brain injury.•ACSL4 promoted neuronal ferroptosis and microglia-mediated neuroinflammation. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme for polyunsaturated fatty acids (PUFAs) metabolism that dictates ferroptosis sensitivity. The role of ACSL4 in the progression of ischemic stroke is unclear. Here, we found that ACSL4 expression was suppressed in the early phase of ischemic stroke and this suppression was induced by HIF-1α. Knockdown of ACSL4 protected mice against brain ischemia, whereas, forced overexpression of ACSL4 exacerbated ischemic brain injury. ACSL4 promoted neuronal death via enhancing lipid peroxidation, a marker of ferroptosis. Moreover, knockdown of ACSL4 inhibited proinflammatory cytokine production in microglia. These data identify ACSL4 as a novel regulator of neuronal death and neuroinflammation, and interventions of ACSL4 expression may provide a potential therapeutic target in ischemic stroke.