Resveratrol promotes diabetic wound healing by inhibiting ferroptosis in vascular endothelial cells

BACKGROUND: Diabetic wounds are a common complication of diabetes, with alarming disability and mortality rates. Ferroptosis plays an essential role in the occurrence and development of diabetes mellitus and its complications, suggesting that mitigating ferroptosis can be used as a potential therapeutic strategy. Resveratrol (RSV) can promote the angiogenesis of diabetic wounds, but its molecular mechanism is unclear, and RSV has a role in regulating ferroptosis. Therefore, we speculated that RSV could promote the angiogenesis of diabetic wounds and accelerate wound healing by regulating ferroptosis. METHODS: In this study, we investigated the effects of RSV on human umbilical vein endothelial cells (HUVECs) treated with advanced glycation end-products (AGEs), focusing primarily on cell proliferation and markers associated with ferroptosis. The methods employed included the CCK-8 assay for cell proliferation, ROS determination, Fe²⁺ measurement, scratch and tube formation assays, and transcriptome analysis. To evaluate the effectiveness of RSV in promoting wound healing, we established a type 2 diabetes rat model and created a skin injury model. Wound healing rates were assessed, and tissue samples were analyzed using hematoxylin and eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Western blotting. Additionally, levels of glutathione (GSH) and malondialdehyde (MDA) were measured to evaluate oxidative stress and lipid peroxidation. RESULT: Upon treatment of HUVECs with AGEs, we observed a decrease in cell viability and induction of ferroptosis. RSV can alleviate ferroptosis in AGEs-treated HUVECs. Further investigation through transcriptome analysis and Western blotting revealed that RSV alleviates ferroptosis in AGE-treated HUVECs by modulating the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). In vivo experiments using a diabetic rat skin injury model confirmed that both RSV and Ferrostatin-1 (Fer-1) enhance wound healing and angiogenesis. This effect was associated with the regulation of ferroptosis marker proteins including GPX4, SLC7A11, and ACSL4. Additionally, in the diabetic rat groups treated with RSV and Fer-1, we noted increased expression of Nrf2, vascular endothelial growth factor (VEGF), and CD31 proteins compared to the diabetic rat control group. CONCLUSION: In diabetic wounds, AGEs can lead to ferroptosis in HUVECs. RSV can inhibit AGE-induced ferroptosis in HUVECs, further promoting angiogenesis in diabetic wounds, and ultimately accelerating wound healing.