Abstract
Air pollution has been increasingly linked to a wide range of diseases, yet the underlying biological mechanisms remain poorly understood. Here, we systematically investigate how circulating proteins mediate the health effects of multiple air pollutants and quantify individual susceptibility. Using large-scale data from the UK Biobank, we identify 30 diseases significantly associated with air pollution exposure. We uncover 1,089 pollutant-associated proteins enriched in immune pathways, among which 296 significantly mediate disease risk. Notably, the mediating pathways of air pollution vary by disease types, involving MAPK signaling in cardiovascular diseases, innate immunity in immune disorders, carbohydrate metabolism in metabolic diseases, and cell proliferation in respiratory conditions. Globally, the proteome mediates 23.69% of the association between air pollution and diseases. Based on these mediators, we develop an Air Pollution Protein Risk Score (APPRS), which shows robust associations with disease risk in the UKBB and two external validation cohorts. APPRS also improves disease prediction when integrated into baseline models. Collectively, our study highlights the central role of circulating proteins in mediating the health impacts of air pollution and introduces APPRS as a tool for personalized risk assessment and precision public health interventions.