Assessing the Toxicological Impact of 6PPD-Quinone on Age-Related Cataract: Insights from Network Toxicology and Molecular Docking

Abstract

Age-related cataract (ARC) is driven by progressive oxidative damage and apoptosis in lens epithelial cells, yet the contribution of urban contaminants remains uncertain. 6PPD-quinone (6PPD-Q), an ozone-derived oxidation product of the tire antioxidant 6PPD, is widespread in urban environments and exhibits strong redox activity. Building on our analysis, we used a network toxicology workflow to explore its potential intersection with cataract biology. We predicted a consolidated set of 382 human protein targets and profiled gene expression in anterior lens-capsule transcriptomes from cataract versus control samples, identifying 856 significantly altered genes. Intersecting these datasets yielded nine candidates—AKT1, APAF1, AMD1, DHODH, GABRG2, GSR, MAOB, S100A9, and TRPA1—that formed a connected protein–interaction module enriched for FAD-dependent oxidoreductase activity, glutathione metabolism, arginine and proline metabolism, and apoptosis. Molecular docking supported direct interactions between 6PPD-quinone and all nine proteins, with binding free energies ranging from −6.1 to −9.9 kcal·mol^-1, and the strongest affinities for the mitochondrial oxidoreductases DHODH and MAOB. These systems-level findings outline a plausible mechanism whereby 6PPD-quinone disrupts lens redox homeostasis and cell survival signaling, generating testable hypotheses for cellular and in vivo validation and indicating a potential environmental contributor to lens aging.