Circadian Regulation of m6A RNA Methylation in Migraine: Mechanisms and Therapeutic Implications.

Migraine is a complex neurological disorder showing distinct circadian rhythmicity in its onset and intensity. Attacks often follow daily patterns, suggesting that molecular clock mechanisms modulate neuronal excitability and pain signaling. Recent advances in neuroepigenetics identify RNA modifications particularly N6-methyladenosine (m6A) as rapid regulators of gene expression that respond to circadian cues. Exploring this circadian epitranscriptomic interaction may clarify time-of-day variations in migraine risk and drug response. This review integrates recent molecular and translational studies examining the interplay between m6A RNA methylation, circadian clock genes, and migraine pathophysiology. Evidence from transcriptomic, neurochemical, and pharmacological research was analyzed to understand how rhythmic RNA modifications affect calcitonin gene-related peptide (CGRP) signaling, neuroinflammation, and chronotherapeutic outcomes. Altered timing or function of m6A enzymes disrupts rhythmic transcription of core clock genes, enhancing CGRP release and inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and nitric oxide. These changes heighten neuronal sensitivity and reduce the migraine threshold. Circadian variations in RNA methylation also influence drug-metabolizing enzymes and transporters, contributing to time-dependent differences in the efficacy of triptans, β-blockers, and CGRP antagonists.Integrating circadian and epitranscriptomic insights offers a pathway to precision migraine therapy. Profiling time-specific RNA modifications and tailoring drug administration to biological timing could improve efficacy, minimize side effects, and guide development of novel disease-modifying treatments targeting m6A-regulated pathways.