PFOS Drives Pulmonary Injury via Glycolytic and Oxidative Metabolic Disruption: Multilevel Evidence Integrating Population, Computational, and Experimental Approaches

High Resolution Image Download MS PowerPoint Slide Perfluorooctanesulfonate (PFOS), a pervasive environmental pollutant, threatens respiratory health, though its pulmonary toxicity mechanisms remain unclear. The study integrated NHANES epidemiological data ( n = 1595), computational toxicology (ADMETlab 3.0 and ProTox-3.0), chronic mouse exposure models (0, 5, and 150 μg kg –1 day –1, 12 weeks), multidatabase bioinformatics (CTD and GeneCards), PPI network analysis, and molecular docking (CB-DOCK2). NHANES analysis revealed a significant inverse correlation between serum PFOS and the FEV1/FVC ratio, indicating PFOS-associated airflow obstruction. Crucially, restricted cubic spline regression identified a unified toxicity threshold at 6.54 ng/mL, beyond which FEV1/FVC declined disproportionately. Computational prediction indicated >80% probability of PFOS respiratory toxicity. Animal experiments demonstrated dose-dependent injury: low dose primarily induced fibrosis, while high dose triggered apoptosis (TUNEL + /cleaved-caspase3). Bioinformatics integration identified metabolic dysregulation as the core mechanism, with KEGG enrichment highlighting glycolysis and xenobiotic metabolism. Core target validation showed PFOS bound with high affinity to AOX1 (−9.2 kcal/mol), GPI (−9.3 kcal/mol), PKM (−8.8 kcal/mol), and CYP1A1 (−9.0 kcal/mol) and suppressed Aox1 ( P < 0.01) and Gpi/Pkm mRNA ( P < 0.05). Additionally, PFOS exposure was accompanied by a decrease in GSH levels and an increase in MDA concentration, thereby inducing oxidative stress. PFOS drives pulmonary injury through dual metabolic hijacking: (1) disruption of AOX1-mediated oxidative defense leading to oxidative stress and (2) suppression of the GLUT1-GPI-PKM glycolytic axis. This study establishes AOX1 enzyme activity and the serum lactate/ATP ratio as promising noninvasive biomarkers for the early detection of PFOS-induced lung damage, offering significant insights for environmental health risk assessment.