Exposure to perfluorooctanoic acid promotes lung adenocarcinoma: mechanistic insights from multidimensional network analyses

Perfluorooctanoic acid (PFOA), a persistent environmental pollutant, has been increasingly implicated in lung cancer development, yet the molecular mechanisms linking PFOA exposure to lung adenocarcinoma (LUAD) remain unclear. This study employed an integrated, multidimensional framework combining epidemiology, computational toxicology, network analysis, machine learning, single-cell transcriptomics, and molecular docking to systematically explore the potential associations between PFOA exposure and LUAD pathogenesis. Serum PFOA and PFOS concentrations were analyzed in 5899 participants from the NHANES 2013–2020 dataset. Weighted logistic regression revealed a significant association between PFOA exposure and lung cancer risk (OR = 1.05 per unit increase in ln-transformed PFOA; 95% CI 1.01–1.09; p = 0.02), whereas PFOS showed no significant relationship. ADMETlab and ProTox predictions indicated multi-organ toxicity and carcinogenic potential of both compounds. Integrative toxicogenomics identified 248 overlapping genes between PFOA targets and LUAD differentially expressed genes, with protein–protein interaction analysis highlighting 20 hub genes. Functional enrichment implicated cell cycle regulation, chromosomal segregation, and p53 signaling as key pathways. A machine learning framework consistently identified CDCA8, TRIP13, CCNB2, and CDC20 as core diagnostic biomarkers with high sensitivity and specificity (AUC > 0.90). Single-cell RNA sequencing revealed these genes were predominantly expressed in malignant epithelial and myeloid cells. Molecular docking confirmed stable, high-affinity interactions between PFOA and the four core proteins. Finally, a prognostic model based on six PFOA-LUAD-associated genes (GJB3, CPS1, EXO1, PLEK2, KRT6A, CDC25C) demonstrated robust predictive performance across multiple independent cohorts (average C-index = 0.763). Collectively, these findings provide novel mechanistic insights into the potential role of environmental PFOA exposure in LUAD development and identify potential diagnostic and prognostic biomarkers. The results have important public health implications, underscoring the need for regulatory measures to reduce PFAS exposure and informing risk assessment, early detection, and targeted intervention strategies.