Glutaredoxin 2 Protects Lens Epithelial Cells From Ferroptosis by Preventing HNRNPA2B1 S-Glutathionylation in Diabetes-Mediated Cataractogenesis

Purpose: The purpose of this study was to investigate the role of glutaredoxin 2 (Grx2) in regulating ferroptosis under oxidative stress conditions induced by high glucose in lens epithelial cells (LECs) and its potential contribution to diabetes-mediated cataractogenesis. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to investigate proteins S-glutathionylation under high glucose condition, with validation by co-immunoprecipitation (Co-IP). Lentiviral transduction, Western blotting, FerroOrange, reactive oxygen species (ROS), and glutathione (GSH) measurements were applied to elucidate the downstream mechanisms. Results: High glucose-induced oxidative stress triggered ferroptosis in the LECs, thereby accelerating diabetes-mediated cataractogenesis. LC-MS/MS and Co-IP analysis identified HNRNPA2B1 as a Grx2-regulated target protein exhibiting increased glutathionylation. This modification regulated PTEN/AKT signaling, leading to mitochondrial dysfunction and subsequent ferroptosis induction. Conclusions: Grx2 exerts protective effects against ferroptosis in diabetes-mediated cataractogenesis by inhibiting HNRNPA2B1 S-glutathionylation and modulating PTEN/AKT signaling pathway.