Preclinical study reveals FOXO6 drives retinal epithelial ferroptosis via SMURF2 and NR4A1 in diabetic retinopathy models, indicating a therapeutic pathway to prevent vision loss.
Key Points
To investigate the upstream regulatory mechanisms controlling retinal pigment epithelial cell ferroptosis under hyperglycemic conditions in diabetic retinopathy.
Examined high glucose-treated human ARPE-19 cells and a diabetic mouse model.
Assessed ferroptosis, iron accumulation, and lipid peroxidation using biochemical assays, Western blotting, fluorescence probes, and histological staining.
Evaluated molecular interactions and transcriptional regulation via co-immunoprecipitation, GST pull-down, chromatin immunoprecipitation, and luciferase reporter assays.
High glucose upregulated NR4A1 in ARPE-19 cells, whereas NR4A1 knockdown reduced iron accumulation, lipid peroxidation, and ferroptosis markers.
SMURF2 directly bound NR4A1 to promote its ubiquitination and degradation, while high glucose-induced FOXO6 repressed SMURF2 transcription.
SMURF2 overexpression mitigated high glucose-induced ARPE-19 ferroptosis and mouse retinal injury, which was reversed by NR4A1 co-overexpression or SMURF2 knockdown.