Association of urinary polycyclic aromatic hydrocarbon metabolites with idiopathic membranous nephropathy: Evidence from case-control and network toxicology.

The environmental factors underlying idiopathic membranous nephropathy (IMN) remain inadequately comprehended. Our purpose is to investigate the environmental factors that contribute to the IMN. Polycyclic aromatic hydrocarbons (PAHs) as a major harmful component of airborne particulate matter, are suspected to be associated with IMN. We employed a 1:1 pair-matched case-control, network toxicology and molecular docking to validate the role of urinary PAHs metabolites in IMN pathogenesis. Urine samples from 146 IMN patients and 146 controls were analyzed for six monohydroxylated PAHs using UPLC-MS/MS. The creatinine-adjusted 1-hydroxynaphthalene (1-OHNAP), 2-hydroxynaphthalene (2-OHNAP), total hydroxynaphthalene (∑OHNAP), and total OHPAHs (∑OHPAHs) were significantly higher in IMN patients (P < 0.05) with odds ratios of 1.42, 1.66, 1.29, and 1.19 respectively, indicating a significantly increased risk of IMN. 8-OHdG were higher in the IMN group. Subgroup analyses indicated stronger associations among males and drinkers. The RCS curve shows that PAHs concentration increases, the risk of IMN generally rises. (P < 0.05). Integrated network toxicology and molecular docking identified TGFβ1 as a key potential target. Molecular dynamics simulations confirmed a stable binding interaction between 2-OHNAP and TGFβ1. This finding was further supported by external RNA-seq data showing elevated TGFβ1 expression in the glomeruli of IMN patients. We report novel evidence suggesting that exposure to PAHs may contribute to the risk of IMN by disrupting immune system, highlighting the environmental factors driving IMN and offering potential therapeutic targets for this increasingly prevalent glomerular disease.