Resveratrol alleviated diabetic retinal neuronal ferroptosis induced by high glucose through inhibiting HIF-1α and HMOX1 pathway.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus that can cause blindness and affect the life quality of patients. Diabetic retinal neurodegeneration (DRN) caused by high glucose might be the earlier pathological change preceding vascular injury. Resveratrol has been showed to have therapeutic effects on DRN but the mechanism remains unclear. Ferroptosis is a new form of regulated cell death and has been found to be involved in DRN. In this study, we found genetic relationship between resveratrol and ferroptosis in DRN pathogenesis using bioinformatics analysis and demonstrated HIF-1α and HMOX1 as the hub genes. Our study established in vitro model of DRN in high-glucose cultured SH-SY5Y cells and found ferroptosis processes characterized of reactive oxygen species (ROS) accumulation and cellular mitochondrial damage along with upregulation of HIF-1α and HMOX1. Application of resveratrol alleviated high glucose-induced ferroptosis phenotypes in SH-SY5Y cells through inhibiting HIF-1α and HMOX1. We also confirmed ferroptosis process and RGC damage in diabetic (db/db) mouse model. The upregulation of HIF-1α and HMOX1 was also found in diabetic mouse retina. By resveratrol gavage, RGC damage in diabetic (db/db) mouse model was alleviated and the expression level of HIF-1α and HMOX1 in retina was decreased. Our study revealed the involvement of ferroptosis process in retinal neurodegeneration and might provide new insights into neuroprotective interventions in diabetic retinopathy.