Integrated plasma proteomics and metabolomes reveal potential biomolecules linking PM2.5 to depression

The biomolecular pathways linking fine particulate matter (PM2.5) and its constituents to depression remain elusive. With 24,940 depression-free participants in the UK Biobank, exposure to PM2.5 and its 5 constituents (ammonium, nitrate, sulfate, elemental carbon, and organic carbon) was estimated. We integrated Olink-based proteomics and NMR-based metabolomics using Cox proportional hazards models, mediation analyses, functional enrichment analyses, and drug predictive analyses. We identified 982 depression cases during a mean follow-up of thirteen years. PM2.5 and its constituents was associated with increased depression risk, with HRs up to 1.20 per SD increment in ammonium. We identified 140 proteins and 3 metabolites as statistically-significant mediators, with mediation proportions up to 8.00% and 3.42%. These mediators were enriched in lipid and unsaturated fatty acid metabolism, immune regulation, and inflammation responses. Drug predictive analyses showed potential drug repurposing. Shifts in biomolecules partially explained PM2.5–depression associations, highlighting inflammation and lipid dysregulation as potential pathways.