Exposure risks of polycyclic aromatic hydrocarbons and potential targets and mechanisms for lung and skin cancer induction: An integrated study based on GBD 2021 and computational toxicology

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogens with significant but poorly quantified global health impacts. Integrating Global Burden of Disease (GBD) 2021 data, network toxicology, molecular simulations, and animal validation, this study systematically reveals the carcinogenic mechanisms of PAHs. Analyses show a marked increase in PAH-attributable disability-adjusted life years (DALYs) for lung and skin cancers from 1990 to 2021, with the highest burden concentrated in rapidly industrializing regions such as China. Age-stratified trends indicate exponentially elevated risks in the elderly, suggesting cumulative exposure effects. Multi-platform bioinformatics identifies TP53, TNF, MMP9, and INS as core targets mediating PAH toxicity, functionally enriched in oxidative stress, inflammation, and extracellular matrix reorganization. Molecular docking and dynamics simulations demonstrate stable, high-affinity PAH-target interactions driven by hydrophobic and hydrogen bonds. Animal experiments further confirm that benzo[ a ]pyrene (BaP) induces pulmonary damage and upregulates key targets (TNF-α, INSR, EGFR, KRAS, IL6), validating predicted mechanisms. Notably, previously unrecognized PAH-nuclear receptor interactions indicate potential endocrine-disruption effects. This work establishes a novel framework linking population-level disease patterns to molecular pathogenesis, offering biomarkers for exposure monitoring and precision prevention strategies to mitigate cancer risks in high-exposure populations. • Global burden of PAH-induced lung/skin cancer rose sharply, especially in aging populations and industrializing regions. • Integrated toxicology identifies TP53, TNF, and INS as core targets in PAH-linked carcinogenesis across cancers. • Molecular docking/dynamics confirm stable binding of PAHs to key targets via hydrophobic and H-bond interactions. • In vivo validation shows BaP exposure upregulates TNF-α, INSR, EGFR, KRAS, IL6 and induces lung damage in mice.