ACSL4 通过促进铁死亡诱导的脑损伤和神经炎症加重缺血性脑卒中。
ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation.
机构信息
Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Ningxia Road 308, Qingdao 266071, Shandong, China.
Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China.
出版信息
Brain Behav Immun. 2021 Mar;93:312-321. doi: 10.1016/j.bbi.2021.01.003. Epub 2021 Jan 11.
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.
酰基辅酶 A 合成酶长链家族成员 4（ACSL4）是多不饱和脂肪酸（PUFAs）代谢的重要同工酶，决定了铁死亡的敏感性。ACSL4 在缺血性中风进展中的作用尚不清楚。在这里，我们发现 ACSL4 的表达在缺血性中风的早期阶段受到抑制，这种抑制是由 HIF-1α 诱导的。ACSL4 的敲低可保护小鼠免受脑缺血，而 ACSL4 的强制过表达则加剧了缺血性脑损伤。ACSL4 通过增强脂质过氧化（铁死亡的一个标志物）促进神经元死亡。此外，ACSL4 的敲低抑制了小胶质细胞中促炎细胞因子的产生。这些数据表明 ACSL4 是神经元死亡和神经炎症的一个新的调节因子，ACSL4 表达的干预可能为缺血性中风提供一个潜在的治疗靶点。
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