Insights into the lactylation-immune regulatory axis as a mechanistic bridge in migraine pathophysiology
Abstract
Wang and colleagues reported a multi-omics Mendelian randomization framework linking a lactylation–immune mediation pathway to migraine risk, nominating EP300, SIRT1, and SLC16A1 as putative causal drivers and highlighting B-cell and NKT-cell phenotypes as mediators. We commend this integrative approach and seek clarification on four points to sharpen mechanistic interpretation and translational planning. First, given the pleiotropic roles of EP300 and SIRT1 across post-translational modifications, what evidence specifically implicates histone lactylation as the primary mechanism in migraine-relevant cells? Second, how should peripheral immune mediation be weighed against potential contributions from central immune populations, and could shared genetic instruments affect both compartments? Third, single-cell RNA sequencing of peripheral blood suggests robust EP300 signals but limited differential expression for SIRT1 and SLC16A1; we ask whether sample size, transcript–protein discordance, or state-dependent effects in rare subpopulations explain this discrepancy. Finally, we explore clinical heterogeneity and potential applications, including whether this axis maps onto distinct migraine subtypes and how it might complement or augment current targeted therapies. Clarifying these issues could guide biomarker selection, endotype enrichment, and mechanistically anchored validation studies in future research.
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