Nomilin ameliorates perfluorooctanoic acid (PFOA)-induced impairment of zebrafish (Danio rerio) ocular development and visual function through PIK3CA activation.

Perfluorooctanoic acid (PFOA), a pervasive environmental contaminant, is implicated in ocular diseases through prenatal/embryonic exposure. This study investigated the protective effects of nomilin, a citrus-derived bioactive compound with therapeutic properties, against PFOA-induced ocular and visual impairments in zebrafish. Integrating network toxicology and molecular docking, we identified seven shared targets (including PIK3CA and mTOR) linking PFOA, nomilin, and ocular diseases. Experimental results demonstrated that PFOA exposure suppressed the PIK3CA/AKT/mTOR/pax6 axis, significantly downregulated (by approximately 0.23- to 0.65-fold) ocular development genes (rx1, vsx1, rpgra, lhx4), and induced structural defects (reduced eye size, lens diameter and retinal layer thickness) and visual dysfunction. Nomilin treatment dose-dependently reversed these effects by activating the PIK3CA/AKT/mTOR/pax6 axis, restoring the expression of ocular developmental related genes by 1.45- to 2.85-fold compared to the PFOA-exposed group, improving ocular morphology, and enhancing visual response behaviors. Furthermore, nomilin attenuated PFOA-induced apoptosis. These findings reveal that nomilin mitigates PFOA-mediated ocular toxicity via PIK3CA activation, offering novel therapeutic insights for environmental pollutant-related ocular disorders.