Hui Zhang, Minming Shao, Feng Zhang, Can He, Jiabi Li, Shengdong He
Abstract Background Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated m 6 A methylation has emerged as a critical epigenetic regulator in neuroinflammatory responses. This study aims to investigate the role of METTL3 in migraine, focusing on its m 6 A-dependent regulatory mechanisms. Methods A rat migraine model was induced via chronic intermittent nitroglycerin administration. Behavioral tests assessed migraine-like symptoms. Protein and RNA levels of METTL3, miR-34a-5p, and downstream targets were analyzed using Western blot, qPCR, ELISA, and immunofluorescence. The interaction among METTL3, miR-34a-5p, and Wnt1 was validated through Co-IP, RIP, and luciferase reporter assays. Results METTL3 expression was significantly upregulated in the trigeminal ganglia of migraine rats. Knockdown of METTL3 reduced trigeminovascular system (TGVS) activation and alleviated migraine symptoms. Mechanistically, METTL3 enhanced miR-34a-5p expression via m 6 A modification, leading to suppression of the Wnt1/β-catenin pathway. Overexpression of miR-34a-5p further aggravated migraine-related responses by inhibiting Wnt1 signaling. Conclusion METTL3 contributes to migraine pathogenesis through m 6 A-dependent upregulation of miR-34a-5p, which suppresses the Wnt1/β-catenin axis and promotes TGVS activation. Targeting this pathway may offer new therapeutic avenues for migraine.