Resveratrol Promotes Wound Healing by Enhancing Angiogenesis via Inhibition of Ferroptosis

Abstract

ABSTRACTDiabetic wound healing critically depends on functional endothelial cells for angiogenesis, yet the hyperglycemic microenvironment induces endothelial dysfunction through oxidative stress, inflammation, and senescence. Although ferroptosis has been recognized as a critical pathological factor contributing to impaired diabetic wound healing, the therapeutic potential of resveratrol (Res), a natural polyphenol with well‐documented antioxidant and anti‐ferroptotic properties, remains underexplored in this context. This study aimed to investigate the protective effects of Res on endothelial cells and elucidate its underlying mechanisms in diabetic wound healing. In vitro experiments systematically evaluated Res's impact on cellular inflammatory responses, senescence levels, and angiogenic capacity. Subsequent in vivo studies assessed Res's therapeutic potential by monitoring diabetic wound healing progression and analyzing associated histological changes. To clarify the mechanisms underlying Res's promotion of diabetic wound healing, we conducted comprehensive analyses measuring intracellular reactive oxygen species, lipid peroxidation levels, mitochondrial membrane potential and morphology, ferroptosis‐related marker expression, and upstream signaling pathway regulation. Res significantly reduced HG‐induced inflammatory responses and cellular senescence in human umbilical vein endothelial cells while enhancing their angiogenic potential in vitro. In vivo results showed that Res not only markedly accelerated diabetic wound healing but also demonstrated multiple beneficial effects, including effective suppression of cellular senescence, decreased ferroptosis levels, and significantly promoted angiogenesis. Mechanistic investigations confirmed that Res achieves these effects by inhibiting ferroptosis through activation of the PI3K‐AKT‐Nrf2 signaling axis. Our results demonstrate that Res protects endothelial cells from HG‐induced ferroptosis by activating PI3K‐AKT‐Nrf2 signaling, thereby promoting angiogenesis and diabetic wound healing. These findings highlight Res as a promising therapeutic candidate for impaired diabetic wound repair and justify further clinical investigation.