Inhibition of the METTL3/m6A/miR-34a-5p axis suppresses trigeminovascular activation in nitroglycerin-induced migraine via the Wnt/β-catenin pathway.

BACKGROUND

Neuroinflammation is a key driver of migraine pathogenesis, particularly by promoting neuronal sensitization. METTL3-mediated m6A 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 m6A-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 m6A 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 m6A-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.