363: Migraine and Lactylation

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Acute headache, Imaging (e.g. fMRI, PET, MRS)

Background and Aims: Lactylation is emerging as a critical link between cellular metabolism and gene regulation, yet its causal role in migraine pathophysiology remains unclear.

Methods: We constructed genetic instruments using DNA methylation (mQTL), gene expression (eQTL), and plasma protein (pQTL) data. Two complementary Mendelian randomization (MR) frameworks—summary-data-based MR (SMR) and conventional two-sample MR—were applied to estimate causal effects in two independent migraine cohorts: the FinnGen consortium (discovery, 55,116 cases) and a large meta-analysis (replication, 13,971 cases). Bayesian colocalization was used to distinguish shared causal variants from linkage disequilibrium. To dissect pathway mechanisms, we performed a two-step MR mediation analysis using genome-wide plasma metabolomics data to quantify the indirect effects of prioritized genes via circulating metabolites.

Results: Multi-omics analyses consistently identified EP300, SIRT1, and SLC16A1 as robust causal candidates. Genetically predicted upregulation of EP300 was associated with increased migraine risk, whereas SIRT1 and SLC16A1 exhibited protective or variable associations. Mediation analyses revealed that EP300 acts as a central "metabolic-epigenetic hub," exerting its effects through diverse systemic metabolic mediators. Specifically, isovalerylglycine, phosphoethanolamine, 5-hydroxylysine, and the glucose-to-mannose ratio were identified as significant mediators, with individual mediation proportions reaching approximately 18–22% in the replication cohort. In contrast, SIRT1 and SLC16A1 showed limited or no consistent metabolite-mediated pathways across cohorts.

Conclusions: Our study implicates EP300 as a key driver of migraine susceptibility. By modulating pathways involving branched-chain amino acid catabolism, membrane phospholipid homeostasis, and N-glycosylation precursors, the EP300-metabolism network bridges the gap between metabolic dysfunction and epigenetic plasticity, highlighting potential targets for precision therapeutic intervention.

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Presenting Author: Zongbin Jiang MD
Submitting Author: Zongbin Jiang

Senior Author: Zongbin Jiang MD

IASP 2026 Global Year theme of Neuropathic Pain: Yes