Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway.

Autor:	Zhan M; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Liu D; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Yao L; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China., Wang W; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Zhang R; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Xu Y; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Wang Z; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Department of Anesthesiology, Ningbo First Hospital, Ningbo, China., Yan Q; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China., Fang Q; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China., Du J; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.; Infectious Disease Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, China., Chen L; Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
Jazyk:	angličtina
Zdroj:	Transplantation [Transplantation] 2024 Nov 01; Vol. 108 (11), pp. e357-e369. Date of Electronic Publication: 2024 May 10.
DOI:	10.1097/TP.0000000000005036
Abstrakt:	Background: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. Methods: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. Results: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury. Conclusions: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury. Competing Interests: The authors declare no conflicts of interest. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Databáze:	MEDLINE
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