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Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway
Mengting Zhan1,2, Deng Liu1,2, Lei Yao3
1Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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.
Insights
Activating AXL receptor tyrosine kinase (AXL) protects the liver from ischemia/reperfusion (I/R) injury by inhibiting ferroptosis via the PI3K/AKT pathway. This offers a novel therapeutic strategy for liver surgery complications.
Area of Science:
- Hepatology and Transplant Surgery
- Molecular Biology and Signaling Pathways
- Cellular Injury and Death Mechanisms
Background:
- Hepatic ischemia/reperfusion (I/R) injury is a significant clinical challenge in liver surgery.
- AXL receptor tyrosine kinase (AXL) expression is elevated in liver transplant patients, but its role in I/R injury is unknown.
- Understanding AXL's mechanism in hepatic I/R injury is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role of AXL activation and ferroptosis in hepatic I/R injury.
- To elucidate the underlying molecular mechanisms involving the PI3K/AKT pathway.
- To determine if AXL activation can serve as a therapeutic target.
Main Methods:
- Established mouse liver warm I/R and primary hepatocyte hypoxia/reoxygenation models.
- Utilized recombinant mouse growth arrest-specific protein 6 (AXL activator) and R428 (AXL inhibitor).
- Employed LY294002 (PI3K inhibitor) to assess the PI3K/AKT pathway's involvement.
Main Results:
- Hepatic I/R injury reduced AXL phosphorylation and increased ferroptosis.
- AXL activation significantly attenuated lipid peroxidation and ferroptosis in vitro and in vivo.
- AXL inhibition worsened liver damage, dysfunction, iron accumulation, and lipid peroxidation.
- Activated AXL/PI3K/AKT signaling inhibited ferroptosis during hepatic I/R.
Conclusions:
- AXL activation protects against hepatic I/R injury by preventing ferroptosis via the PI3K/AKT pathway.
- This study is the first to link AXL receptor signaling with ferroptosis in hepatic I/R injury.
- Activating AXL presents a potential innovative therapeutic strategy for mitigating hepatic I/R injury.
