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

📖 Top 20% JournalJan 20, 2026Journal of molecular neuroscience : MN

Daily Rhythms of RNA Modification in Migraine: How It Works and Possible Treatments

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Migraine attacks often follow daily patterns, suggesting that molecular clock mechanisms may influence their onset and intensity.

Migraine is associated with distinct circadian rhythms in its onset and intensity.
RNA modifications, particularly N6-methyladenosine (m6A), rapidly regulate gene expression in response to circadian cues.
Altered function of m6A enzymes may disrupt the rhythmic transcription of core clock genes, leading to increased release of migraine-related molecules.
Changes in RNA methylation influence the signaling of calcitonin gene-related peptide (CGRP) and inflammatory markers, potentially heightening neuronal sensitivity.
Circadian variations in RNA methylation could affect the metabolism of migraine medications, leading to differences in their effectiveness throughout the day.
Integrating insights from circadian biology and RNA modifications may enhance the development of personalized migraine therapies.

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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.

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