Methylparaben Exposure and Keratoconus: A Mechanistic Study Integrating Mendelian Randomization, Network Toxicology, Molecular Docking, and Experimental Validation

Parabens are widely used preservatives, yet their association with keratoconus (KC) remains unclear. Here, we combined Mendelian randomization (MR), network toxicology, molecular docking, molecular dynamics simulations, and cell-based assays to investigate this relationship. MR analysis indicated that, among the four parabens evaluated, only methylparaben (MPB) was genetically associated with KC. Network toxicology identified 139 overlapping database-derived candidate genes potentially linking MPB and KC, with AKT1 and FN1 prioritized as computational hub candidates, enriched in pathways linked to hypoxia, ECM organization, and estrogen signaling. Molecular docking and dynamics simulations predicted favorable binding poses of MPB to both AKT1 and FN1. In cultured corneal stromal cells, MPB dose-dependently increased oxidative stress, suppressed AKT phosphorylation, and reduced FN1 and collagen I levels, recapitulating several features of a KC-associated cellular phenotype. Our findings suggest MPB as a potential risk factor for KC and identify AKT1 and FN1 as candidate molecular targets. These results offer a hypothesis-generating basis for evaluating the ocular safety of MPB-containing products and point to a previously overlooked environmental contributor to KC.