Perfluorooctanesulfonic acid contributes to primary open-angle glaucoma in a FABP4-Dependent manner: a novel mechanism for environmental risk of glaucoma

Background Primary open-angle glaucoma (POAG) is the most prevalent form of glaucoma globally, with environmental factors increasingly recognized as critical determinants of its onset and progression. However, the potential association between perfluorooctanesulfonic acid (PFOS) exposure and POAG remains poorly understood, and its underlying molecular mechanisms have yet to be elucidated. Methods and results Utilizing cross-sectional data from the NHANES database, we identified a significant positive correlation between serum PFOS levels and glaucoma prevalence. The robustness of our study population selection and the focus on POAG were further validated through the Global Burden of Disease (GBD) database and systematic literature review. Network toxicology analysis identified 20 PFOS-exposure-related genes in POAG, with functional enrichment highlighting the biosynthesis of unsaturated fatty acids as a key pathway. Integrated machine learning and bioinformatic analysis pinpointed FABP4 as a pivotal candidate gene. Molecular docking and dynamics simulations confirmed stable binding affinity between PFOS and the FABP4 protein. In vitro experiments using human trabecular meshwork cells (HTMCs) demonstrated that PFOS exposure induced cellular senescence, as evidenced by SA-β-gal staining. Western blot analysis revealed that PFOS significantly upregulated the expression of FABP4 and the senescence marker P21. Crucially, targeted functional inhibition of the FABP4 protein successfully rescued PFOS-induced senescence and downregulated P21 expression. Conclusion These findings provide novel insights into the toxicological profile of PFOS, suggesting that it contributes to POAG pathogenesis by modulating FABP4-mediated cellular senescence. This study offers a theoretical basis for environmental risk assessment and the development of preventive strategies for POAG.