期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 20, 期 6, 页码 1606-1618出版社
WILEY
DOI: 10.1111/ajt.15773
关键词
cell death; liver transplantation; hepatology; liver transplantation; living donor; translational research; science
资金
- JMU
- Smoking Research Foundation in Japan
- Japan Society for the Promotion of Science (JSPS) [18K08112]
- Takeda Science Foundation
- Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST)
- Japan Society for the Promotion of Science [18K08112]
- Smoking Research Foundation
- Jichi Medical University
- Core
- Grants-in-Aid for Scientific Research [18K08112] Funding Source: KAKEN
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 alpha-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.
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