Metrnl/C-KIT Axis Attenuates Early Brain Injury Following Subarachnoid Hemorrhage by Inhibiting Neuronal Ferroptosis

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2025 Feb 21

PMID 39981761

Authors

You Zhou

Jiani Li

Ye Yuan

Hao Zhang

Xu Luo

Feng Wang

Yihao Tao

Jianhe Yue

Luyi Huang

Lei Wu

Yunxing Cao

Qian Yu

Qiuguang He

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Ferroptosis is a distinct form of cell death characterized by iron-dependent lipid peroxidation and plays a crucial role in the early brain injury (EBI) following subarachnoid hemorrhage (SAH). As a newly discovered endogenous ligand for the C-KIT receptor tyrosine kinase, meteorin-like protein (Metrnl) exerts regulatory functions in oxidative stress and protects against various diseases. However, the specific role of the Metrnl/C-KIT axis in neuronal ferroptosis during EBI following SAH remains to be elucidated.

Methods: Sprague Dawley rats were used to establish the SAH model through endovascular perforation. r-Metrnl was administered intranasally 1 h after SAH. Metrnl shRNA, C-KIT inhibitor ISCK03, AMPK inhibitor dorsomorphin, and Nrf2 inhibitor ML385 were administered intracerebroventricularly or intraperitoneally before r-Metrnl treatment to explore the underlying mechanisms. Neurobehavioral assessments, immunofluorescence, western blot, ELISA, Fluoro-Jade C staining, transmission electron microscopy, and Nissl staining were conducted to evaluate the effects. Additionally, primary neuron culture with hemoglobin (Hb) stimulation was used for in vitro studies.

Results: Phosphorylated C-KIT and endogenous Metrnl levels were upregulated after SAH. Knockdown of Metrnl aggravated neurobehavioral deficits and neuronal ferroptosis, whereas r-Metrnl treatment showed a protective effect. Mechanistically, r-Metrnl significantly increased the protein levels of SLC7A11, GPX4, FTH, FSP1, and GSH, whereas it decreased the levels of ACSL4, 4HNE, and MDA in the ipsilateral hemisphere 24 h after SAH. Also, r-Metrnl reduced mitochondrial shrinkage, increased mitochondrial crista, and decreased membrane density. However, the beneficial effects of r-Metrnl were partially reversed by ISCK03, dorsomorphin, or ML385 treatment both in vivo and in vitro.

Conclusions: Our study demonstrated that r-Metrnl reduced neuronal ferroptosis and improved neurological outcomes after SAH by modulating the C-KIT/AMPK/Nrf2 signaling pathway.

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