Association of Unsaturated Fatty Acid–Related Immunometabolic Features with Differential Responses to Erenumab in Patients with Migraine: An Exploratory Multi-Omics Study

Abstract Background Erenumab, the first calcitonin gene-related peptide (CGRP) receptor-targeting monoclonal antibody approved for migraine prevention in China, has shown substantial clinical benefit in Chinese patients with migraine. However, the degree of improvement varies among individuals. We therefore investigated pretreatment metabolic and transcriptional features associated with differences in erenumab response. Methods In this prospective study, 40 patients with migraine received erenumab 70 mg every 4 weeks for 3 months. Pretreatment whole-blood samples underwent untargeted metabolomics and RNA sequencing. Super-response was defined as a ≥ 75% reduction in monthly headache days at month three; patients not meeting this criterion were classified as non-super-responders. Analyses integrated differential feature screening, metabolite-set enrichment, a UFA-related principal component score, weighted gene co-expression network analysis, and response-group-adjusted gene–metabolite correlations. Molecular docking was exploratory. Results 26 patients (65%) achieved super-response. We identified 52 differential metabolomic features and 297 candidate differentially expressed genes. UFA biosynthesis was enriched toward non-super-responders (normalized enrichment score 2.12; P = 0.00118). Four transcriptional modules were associated with the metabolic score, and 14 genes overlapped these modules and the differential expression set. Across 84 gene–metabolite correlations, the feature annotated as strophanthidin was inversely associated with PREX1, MYADM, BCL3, and KDM6B (partial rho − 0.52 to − 0.48; P = 0.0418 for each). These four genes showed higher expression in non-super-responders than in super-responders. Gene-centered enrichment identified overlapping pathways related to immune function, and exploratory docking characterized potential interactions between erenumab and proteins encoded by the four candidate genes. Conclusions We identified UFA-related metabolic variation associated with non-super-responder versus super-responder status in erenumab-treated migraine patients. Four candidate genes were inversely associated with a shared mass-spectrometry feature. These findings provide new molecular insights into response heterogeneity and potential directions for further investigation.