Impaired IFN-γ/STAT1-associated immune regulation contributes to 4-nonylphenol-aggravated allergic rhinitis

4-Nonylphenol (4-NP) is a persistent endocrine-disrupting chemical, but its role in allergic rhinitis (AR) remains poorly understood. The study here integrated human transcriptomics, network toxicology, single-cell analysis, molecular modeling, and experimental validation to investigate the mechanisms underlying 4-NP-aggravated AR. Network analysis identified four shared candidates, e.g., CDKN1A, SKIL, IFNG, and B4GALT1. In an independent cohort, IFNG and SKIL were down-regulated in AR, whereas CDKN1A was increased. Single-cell analysis showed that IFNG was mainly expressed in T-cells. Molecular docking predicted the strongest interaction between 4-NP and IFNγ (−6.4 kcal/mol), and a 50-ns molecular dynamics simulation supported the stability of the predicted complex. In human nasal epithelial progenitor cells (HNEPC), 4-NP increased IL1B, TNF, and IL6 expression. In house dust mite (HDM)-induced AR mice, 4-NP co-exposure increased nasal rubbing, eosinophilic inflammation, TH2 responses, IL-4 production, and inflammatory gene expression, while reducing Ifng expression, TH1 cells, and STAT1 phosphorylation. Recombinant IFNγ partially reversed the TH1/TH2 imbalance and reduced eosinophilic inflammation and IL-4 levels. These findings suggest that 4-NP aggravates AR in association with impaired IFNγ/STAT1-related immune regulation and enhanced nasal epithelial inflammation.