Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury.

中文翻译：

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铁过载作为肝移植中肝缺血再灌注损伤的危险因素：铁死亡的潜在作用。

肝脏缺血再灌注 (I/R) 损伤是肝移植 (LT) 中的主要问题。尽管肝细胞死亡是肝脏 I/R 损伤的初始事件，但其潜在机制仍不清楚。在本研究中，我们回顾性分析了 202 名儿童活体 LT 的临床资料，发现供体血清铁蛋白水平高是铁过载的标志，是 LT 后肝损伤的独立危险因素。由于最近发现铁死亡是由细胞氧化还原稳态丧失引发的铁依赖性细胞死亡，我们研究了铁死亡在肝 I/R 损伤小鼠模型中的作用，发现肝损伤、脂质过氧化、铁死亡标志物 Ptgs2 的上调是由 I/R 诱导的，铁死亡特异性抑制剂 ferrostatin-1 (Fer-1) 或 α-生育酚显着阻止了所有这些表现。Fer-1 还抑制肝 I/R 诱导的炎症反应。此外，肝脏 I/R 损伤因去铁胺的铁螯合作用而减弱，并因高铁饮食的铁过载而加剧。这些发现表明，铁过载是 LT 中肝 I/R 损伤的新危险因素，而铁死亡有助于肝 I/R 损伤的发病机制。