Unveiling the endocrine-disrupting chemicals-lung adenocarcinoma in never-smokers: A mixture exposure and network toxicology study

• First evidence : linking endocrine-disrupting chemicals (EDCs) to lung adenocarcinoma (LUAD) in never-smokers through integrated serum biomonitoring and network toxicology analysis. • Identified high-risk EDCs : Alkylphenols and bisphenols emerged as significant risk categories, with 4‑tert‑octylphenol (4‑tert‑OP) and bisphenol A (BPA) contributed most to LUAD risk. • Non-mediating or modifying effects of inflammation : Systemic inflammation (measured by neutrophil-to-lymphocyte ratio, NLR) neither mediated nor modified EDC-LUAD associations. • Novel mechanistic insights : Uncovered EDC-driven LUAD pathways, including dysregulated ligand-receptor interactions, cell proliferation, endocrine and cancer-related pathways. The incidence of lung cancer in never-smokers (LCINS), predominantly manifesting as lung adenocarcinoma (LUAD) in females, has shown a steady rise. While endocrine-disrupting chemicals (EDCs) represent potential risk factors for LCINS, their specific contributions and underlying toxicological mechanisms remain poorly characterized. We conducted a case-control study involving 196 LCINS cases (including 166 LUAD) and 191 healthy controls. Serum concentrations of 19 EDCs across five categories (alkylphenols, bisphenols, parabens, benzophenones, and antibacterial agents) were quantified. Associations were evaluated using both single-exposure models (logistic regression with FDR adjustment) and mixture exposure models (generalized weighted quantile sum, gWQS) to identify high-risk EDC categories and key individual EDC links to LUAD in never-smokers. Roles of systemic inflammation were assessed through effect modification and mediation analysis, and network toxicology approaches were employed to elucidate pathways and hub genes. EDC mixture showed significant positive associations with LUAD risk in never-smokers, particularly for Σalkylphenols (OR = 1.34, q < 0.05) and Σbisphenols (OR = 1.28, q < 0.05), with 4‑tert‑octylphenol (4‑tert‑OP) and bisphenol A (BPA) identified as key drivers. While neutrophil-to-lymphocyte ratio (NLR) exhibited a dose-dependent relationship with LCINS risk (OR = 1.38, P = 0.007), neither interaction ( P interaction > 0.05) nor mediation ( P mediation > 0.05) effect was observed between key EDCs and NLR. Integrative network toxicology revealed two mechanistic axes for 4‑tert‑OP/BPA-induced LUAD, including ligand-receptor interactions, cell proliferation, endocrine and cancer-related pathways. Hub gene analysis identified ESR1, AKT1, CASP3, and PTGS2 as central to BPA-LUAD associations, and AKT1, PTGS2, ESR1, MMP9, HSP90AA1, and BCL2 implicated in 4‑tert‑OP and LUAD interactions. These hub genes exhibited higher expressions in LUAD tissues and correlated with poor survival (HR > 1, P < 0.05). Our findings implicate alkylphenols (especially 4‑tert‑OP) and bisphenols (notably BPA) as key risk factors for LUAD in never-smokers, operating through endocrine disruption and carcinogenic pathways rather than systemic inflammation. The identified hub genes may serve as potential biomarkers for EDC-associated LUAD risk stratification.