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

IF 5.3 2区医学 Q1 IMMUNOLOGY

Transplantation Pub Date : 2024-11-01 Epub Date: 2024-05-10 DOI:10.1097/TP.0000000000005036

Mengting Zhan, Deng Liu, Lei Yao, Weizhi Wang, Ruixin Zhang, Yaru Xu, Zhen Wang, Qi Yan, Qi Fang, Jian Du, Lijian Chen

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引用次数: 0

Abstract

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.

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Gas6/AXL 通过 PI3K/AKT 通路抑制铁凋亡减轻肝脏缺血/再灌注损伤

背景：肝脏缺血/再灌注（I/R）损伤是临床肝脏手术并发症的主要原因。AXL受体酪氨酸激酶（AXL）是TAM受体酪氨酸激酶家族（TYRO3、AXL和MERTK）的成员。我们之前的研究表明，肝移植患者体内 AXL 的表达明显上调。然而，AXL在肝脏I/R损伤中的潜在机制仍不清楚：方法：通过使用重组小鼠生长停滞特异性蛋白 6（AXL 激活剂）或 R428（AXL 抑制剂）预处理，建立了小鼠肝温热 I/R 模型和原代肝细胞缺氧/再氧模型，以研究 AXL 激活和铁氧化在肝 I/R 损伤中的作用。此外，我们还使用LY294002（磷脂酰肌醇3-激酶[PI3K]抑制剂）评估了PI3K/AKT（丝氨酸和钍激酶AKT）通路与肝脏I/R损伤中铁细胞减少之间的关系：结果：在肝移植患者和肝I/R受试小鼠中，肝I/R损伤降低了磷酸化AXL的表达，增强了铁蛋白沉积。激活 AXL 可减轻体内和体外肝 I/R 损伤中的脂质过氧化和铁蛋白沉积。抑制AXL活化会加重肝脏病理损伤和肝功能异常，以及肝脏I/R损伤中的铁积累和脂质过氧化。从机制上讲，活化的生长停滞特异性蛋白6/AXL及其下游的PI3K/AKT信号通路抑制了肝脏I/R损伤过程中的铁氧化：结论：AXL活化可通过PI3K/AKT通路阻止铁蛋白沉积，从而保护肝脏免受I/R损伤。这项研究是首次对 AXL 受体和铁绒毛膜促性腺激素沉积进行研究，激活 AXL 以减轻铁绒毛膜促性腺激素沉积可能是抗击肝 I/R 损伤的一种创新治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Transplantation 医学-免疫学

CiteScore

8.50

自引率

11.30%

发文量

1906

审稿时长

1 months

期刊介绍： The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.