Integrating Divergence-Based Proteomic Analysis and Directed Network Diffusion to Characterize Diagnosis-Anchored Molecular Variability at the Metabolic Syndrome–Migraine Interface

Metabolic syndrome (MetS) has been associated with migraine, but the prediagnostic phase and the molecular features preceding migraine onset remain unclear. We aimed to identify a diagnosis-anchored proteomic variability window and to characterize pathways, candidate bridge proteins, and druggable targets within a direction-consistent MetS-to-migraine molecular framework. We first assessed the association between baseline MetS and incident migraine in 452,471 UK Biobank participants using Cox models. We then conducted a nested proteomics case–control analysis stratified by MetS status and applied single-sample Jensen–Shannon divergence (sJSD), network proximity, directed diffusion, and drug–target proximity analyses. Baseline MetS was associated with a higher risk of incident migraine (hazard ratio 1.09, 95% confidence interval (CI) 1.01–1.18; p = 0.022). A diagnosis-anchored proteomic divergence pattern peaked 4.71–6.76 years before migraine diagnosis in the MetS stratum. The parallel within-stratum analysis in the NoMetS stratum showed no T2-centered peak. We identified 11 direction-consistent novel pathways, seven candidate bridge proteins spanning metabolic, endothelial, and brain tissues, and three candidate drugs. These findings support a diagnosis-stratified framework for studying MetS-related migraine and provide testable hypotheses for future mechanistic and pharmacological evaluation.