Blue Light Pollution and Ocular Surface Toxicity: p53-Mediated Ferroptosis in Corneal Epithelium Drives Dry Eye Pathogenesis

Purpose: This study investigated the molecular mechanisms underlying blue light-induced corneal epithelial toxicity. Methods: C57BL/6J mice were exposed to 460 nm blue light for 1, 2, or 4 weeks, whereas human corneal epithelial (HCE) cells were exposed for 15 or 30 min. RNA-sequencing with bioinformatic analysis identified p53 signaling and ferroptosis as key pathways. p53 knockdown using siRNA and pharmacological inhibition with pifithrin-α (PFT-α) were employed to validate the mechanism in vitro and in vivo. Results: Blue light exposure caused time-dependent corneal epithelial disruption, reduced tear film stability, increased inflammatory cell infiltration, downregulated K12 expression, and upregulated K10 expression. Blue light induced cell death and G1-phase cell-cycle arrest in HCE cells. Ferroptosis hallmarks included intracellular ferrous iron (Fe2+) accumulation, reactive oxygen species (ROS) generation, decreased SLC7A11 and GPX4 expression, and increased COX2 expression. RNA sequencing revealed p53 pathway activation as a master regulator of ferroptosis. p53 knockdown reversed blue light-induced SLC7A11/GPX4 suppression and COX2 upregulation. Topical PFT-α administration attenuated corneal epithelial damage, restored K12 expression, suppressed K10 expression, and normalized ferroptosis markers in vivo. Conclusions: Blue light pollution triggers corneal epithelial ferroptosis through p53-mediated SLC7A11/GPX4 axis suppression. Pharmacological inhibition of p53 represents a promising therapeutic strategy for blue light-associated dry eye.