Desferrioxamine attenuating high glucose-induced ferroptosis and inflammatory responses in Müller glial cells via Nrf2/TXNRD1 pathway

To investigate the protective effects of deferoxamine (DFO) on high glucose (HG)-induced ferroptosis and inflammatory responses in retinal Müller glial cells (MGCs) and offer potential therapeutic targets for early intervention in diabetic retinopathy (DR).

Primary MGCs were cultured from C57BL/6J mouse retinas and exposed to normal glucose (NG, 5 mmol/L) or HG (25 mmol/L) conditions for various durations. Ferroptosis-related markers, including intracellular Fe²⁺ levels, glutathione (GSH), reactive oxygen species (ROS), malondialdehyde (MDA), and key proteins glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), were examined using multiple assays such as immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), and fluorometric detection. The role of DFO was evaluated through cell viability assessment and analysis of inflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).

HG exposure significantly increased intracellular Fe²⁺ content, decreased GSH levels, elevated ROS and MDA concentrations, and altered expression profiles of ferroptosis regulators GPX4 and SLC7A11. Immunoblot and IF analyses confirmed downregulation of GPX4 and SLC7A11 alongside accumulation of FTH1 under prolonged HG treatment. DFO administration markedly attenuated these ferroptotic changes while reducing inflammatory cytokine secretion, demonstrating its protective effect against HG-induced damage in MGCs by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/thioredoxin reductase 1 (TXNRD1) pathway.

Low-dose DFO effectively mitigates HG-induced ferroptosis and inflammatory responses in MGCs through the Nrf2/TXNRD1 signaling axis, providing a theoretical framework for developing novel therapeutic strategies in DR management.