Inhibition of the METTL3/mA/miR-34a-5p axis suppresses trigeminovascular activation in nitroglycerin-induced migraine via the Wnt/β-catenin pathway.

Abstract

BACKGROUND: Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated mA 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 mA-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 mA 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 mA-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.