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

Authors

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

Published in

Environmental pollution (Barking, Essex : 1987). Pages 129476. Nov 07, 2026. Epub Nov 07, 2026.

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 PM_2.5, NO₂, NO_x, 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 PM_2.5, NO₂, NO_x, and SO₂ was associated with 5%-14% higher T2D risk. We identified 187 proteins mediating the PM_2.5-T2D association, 61 for NO₂, 66 for NO_x, and 14 for SO₂. The protein score mediated 31.69% (PM_2.5), 18.06% (NO₂), 16.81% (NO_x), 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.

PMID:
42998697
Bibliographic data and abstract were imported from PubMed on 08 Nov 2026.

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