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. 2020 Jun;20(6):1606-1618.
doi: 10.1111/ajt.15773. Epub 2020 Feb 3.

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Naoya Yamada  1   2 , Tadayoshi Karasawa  1 , Taiichi Wakiya  3 , Ai Sadatomo  1 , Homare Ito  1 , Ryo Kamata  1 , Sachiko Watanabe  1 , Takanori Komada  1 , Hiroaki Kimura  1 , Yukihiro Sanada  2 , Yasunaru Sakuma  2 , Koichi Mizuta  4 , Nobuhiko Ohno  5   6 , Naohiro Sata  2 , Masafumi Takahashi  1
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Free article

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Naoya Yamada et al. Am J Transplant. 2020 Jun.
Free article

Abstract

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.

Keywords: cell death; liver transplantation/hepatology; liver transplantation: living donor; translational research/science.

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References

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