Environmental pollution (Barking, Essex : 1987) ·7 Nov 2026 ·Added 10 Nov 2026

Plasma proteomic profiling reveals mediating proteins and preventive targets linking ambient air pollution to type 2 diabetes incidence: a prospective cohort study.

Zihan Lin, Dashan Zheng, Peng Hu, Yang Shen, Zilong Zhang, Zhengmin Min Qian, Michael Elliott, Tom Burroughs, Xudong Li, Hualiang Lin

DOI ↗

Abstract

Ambient air pollution has been associated with type 2 diabetes (T2D), but the underlying biological mechanisms remain poorly understood. We included 44,917 participants with 2,911 plasma proteins from a large prospective cohort and followed them for incident T2D. Long-term PM2.5, NO2, NOx, and SO2 exposures were estimated via bilinear interpolation. Cox regressions assessed air pollutant-T2D associations. Elastic net regression identified air pollution-associated proteins and constructed a protein score. Mediation analyses identified top-mediating proteins. Functional and PPI analyses identified hub proteins. Druggability was screened using two drug databases, with binding potential evaluated by molecular docking across seven small-molecule databases. During 13.64 years of follow-up, 3,193 incident T2D cases occurred. Per IQR increase in PM2.5, NO2, NOx, and SO2 was associated with 5%-14% higher T2D risk. We identified 187 proteins mediating the PM2.5-T2D association, 61 for NO2, 66 for NOx, and 14 for SO2. The protein score mediated 31.69% (PM2.5), 18.06% (NO2), 16.81% (NOx), and 19.71% (SO2) of the associations. Functional and PPI analyses revealed these proteins function through cytokine-cytokine receptor interactions, chemokine signaling, leukocyte migration, and inflammation-related pathways. We further identified 13 targeted proteins with approved drugs (4 in DrugBank, 4 in Therapeutic Target Database). Molecular docking indicated 5 have potential small-molecule binders. This study identified potential biological pathways and candidate mediators linking air pollution to T2D, particularly through inflammatory and immune-related pathways mediated by plasma proteins, and identified potential intervention targets, offering opportunities for drug repurposing and precise prevention.