Integrating epidemiology and mechanistic studies links PFAS exposure to ocular diseases and implicates PFOS-associated glaucoma risk through the PI3K/Akt-MMP3 axis.

Perfluoroalkyl substances (PFAS) pose health risks, but their association with glaucoma, cataracts, and age-related macular degeneration remains uncertain. First, a cross-sectional analysis of NHANES (2005-2008) was performed using multiple logistic regression and mixture models, including weighted quantile sum (WQS), quantile g-computation (QGC), and Bayesian kernel machine regression (BKMR), to examine single and mixed PFAS exposures in relation to ocular diseases. Second, Mendelian randomization was applied to further explore the PFOS-glaucoma association. Third, network toxicology and in vitro experiments were employed to generate mechanistic hypotheses. Cross-sectional results suggested positive associations between PFOS and glaucoma, and between PFNA and cataracts. Sex-stratified analyses revealed positive associations of PFOS with glaucoma in females, and in males, of PFDA with glaucoma and PFNA with cataracts. Mixture models suggested that PFOS may be a driving factor for glaucoma risk. Sensitivity analyses yielded results generally consistent with the primary findings. Mendelian randomization supported a positive PFOS-glaucoma association. Network toxicology and in vitro experiments indicated that PFOS activates PI3K/Akt signaling and reduces MMP3 expression. LY294002 treatment partly restored MMP3 expression, supporting a role for PI3K/Akt signaling in this response. These results suggest that the PI3K/Akt-MMP3 axis may be involved in PFOS-induced extracellular matrix changes in trabecular meshwork cells.