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

作者：You Zhou, Jiani Li, Ye Yuan, Hao Zhang, Xu Luo, Feng Wang, Yihao Tao, Jianhe Yue, Luyi Huang, Lei Wu, Yunxing Cao, Qin Yu, Qiuguang He · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1111/cns.70286 · 被引用次数：9 · 研究领域：Ferroptosis and cancer prognosis、Intracerebral and Subarachnoid Hemorrhage Research、Immune cells in cancer

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 o...