Lung ischemia‐reperfusion (IR) injury is a common clinical pathology associated with high mortality. Ferroptosis, a novel mode of cell death elicited by iron‐dependent phospholipid peroxidation, has been implicated in ischemic events. Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) is one of the main enzymes in pro‐ferroptotic lipid metabolism. In this study, the involvement of ferroptotic death in different durations of reperfusion was evaluated by assessing the iron content, malondialdehyde, and glutathione levels, ferroptosis‐related protein expression, and mitochondria morphology. The roles of ferroptosis‐specific inhibitor, liproxastin‐1 (Lip‐1), and ACSL4 modulation in a preventive regimen were assessed in vivo and in vitro. The hallmarks of pulmonary function, such as histological lung injury score, wet/dry ratio, and oxygenation index, were evaluated as well. Results showed that lung IR increased the tissue iron content and lipid peroxidation accumulation, along with key protein (GPX4 and ACSL4) expression alteration during reperfusion. Pretreatment with Lip‐1 inhibited ferroptosis and ameliorated lung IR‐induced injury in animal and cell models. In addition, administering ACSL4 inhibitor rosiglitazone before ischemia diminished the ferroptotic damage in IR‐injured lung tissue, consistent with the protective effect of ACSL4 knockdown on lung epithelial cells subjected to hypoxia/reoxygenation. Thus, this study delineated that IR‐induced ferroptotic cell death in lung tissue and ACSL4 were correlated with this process. Inhibition of ferroptosis and ACSL4 mitigated the ferroptotic damage in IR‐induced lung injury by reducing lipid peroxidation and increasing the glutathione and GPX4 levels.

中文翻译：

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抑制 ACSL4 可减轻肺缺血再灌注后的铁死亡损伤

肺缺血再灌注（IR）损伤是一种常见的临床病理，与高死亡率相关。铁死亡是一种由铁依赖性磷脂过氧化引起的新型细胞死亡模式，与缺血事件有关。酰基辅酶A合成酶长链家族成员4（ACSL4）是促铁凋亡脂质代谢的主要酶之一。在这项研究中，通过评估铁含量、丙二醛和谷胱甘肽水平、铁死亡相关蛋白表达和线粒体形态来评估铁死亡在不同再灌注持续时间中的参与。在体内和体外评估了铁死亡特异性抑制剂、liproxastin-1 (Lip-1) 和 ACSL4 调节在预防方案中的作用。肺功能的标志，如组织学肺损伤评分、湿/干比、和氧合指数，也进行了评估。结果表明，肺 IR 增加了组织铁含量和脂质过氧化积累，以及再灌注过程中关键蛋白（GPX4 和 ACSL4）表达的改变。在动物和细胞模型中，用 Lip-1 预处理可抑制铁死亡并改善肺 IR 诱导的损伤。此外，在缺血前给予 ACSL4 抑制剂罗格列酮减少了 IR 损伤肺组织中的铁死亡损伤，这与 ACSL4 敲低对缺氧/复氧的肺上皮细胞的保护作用一致。因此，该研究描述了 IR 诱导的肺组织和 ACSL4 中的铁死亡细胞死亡与该过程相关。