Dexamethasone sensitizes lens epithelial cells to ferroptosis through the glucocorticoid receptor/nuclear factor erythroid 2-related factor 2 signaling axis.

The aim of this study was to investigate dexamethasone (Dex) involvement in lens epithelial cell (LEC) ferroptosis. A Cell Counting Kit-8 was used to assess LEC viability. Ferroptosis-related indicators were evaluated by measuring the malondialdehyde (MDA) content, intracellular ferrous ion levels, reactive oxygen species (ROS) production, and mitochondrial morphology via transmission electron microscopy. Western blotting and immunofluorescence staining were performed to assess the expression and localization of ferroptosis-related proteins and signaling molecules. In addition, an animal model of ferroptosis-induced cataracts was generated using erastin and Dex to confirm the above results in vivo. Dex alone at high concentrations (100 μmol/L) did not induce ferroptosis in LECs and failed to alter the MDA levels, ferrous ion content, ferroptosis-related protein expression, or ferroptosis-associated mitochondrial morphology, despite dose-dependent reductions in LEC viability. At lower concentrations, 1 μmol/L Dex increased the sensitivity of LECs to erastin-induced ferroptosis, as evidenced by the loss of cell viability and the accumulation of ROS and ferrous ions, the downregulation of ferroptosis-related protective proteins, and the exacerbation of mitochondrial damage. Mechanistically, Dex activated the expression of the glucocorticoid receptor (GR) and promoted its nuclear translocation; pretreatment with a GR antagonist (RU486) reversed Dex-mediated ferroptosis sensitization. Furthermore, Dex-induced GR activation inhibited the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), whereas activating Nrf2 with tert-butylhydroquinone (tBHQ) attenuated erastin- and Dex-induced ferroptosis in vitro and in vivo. In mice, Dex exacerbated erastin-induced cataract formation and LEC ferroptosis, which was reversed by tBHQ treatment. Dex does not directly induce ferroptosis in LECs but instead sensitizes them to ferroptosis through upregulation of the activity of the GR/Nrf2 pathway, leading to cataract formation. Targeting the GR/Nrf2 axis may provide a novel therapeutic strategy for treating glucocorticoid-induced cataracts.