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

  • CNS Neurosci Ther. 2025 Feb;31(2):e70286. doi: 10.1111/cns.70286.
You Zhou  1 ,  Jiani Li  2 ,  Ye Yuan  3 ,  Hao Zhang  3 ,  Xu Luo  3 ,  Feng Wang  3 ,  Yihao Tao  3 ,  Jianhe Yue  3 ,  Luyi Huang  4 ,  Lei Wu  5 ,  Yunxing Cao  1 ,  Qian Yu  6 ,  Qiuguang He  3
Affiliations
  • 1. Department of Critical Care Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 2. Department of Neurology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 3. Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 4. Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 5. Department of Neurology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
  • 6. Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
PMID: 39981761 DOI: 10.1111/cns.70286
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.

Keywords
C‐KIT; Metrnl; ferroptosis; subarachnoid hemorrhage.
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