Targeting ferroptosis promotes diabetic wound healing via Nrf2 activation.

Wound healing impairment is a frequent diabetes problem leading to amputation. Hyperglycemia induces the overproduction of reactive oxygen species (ROS), iron overload and sustained inflammation, resulting in the persistence of chronic wounds. However, the intrinsic mechanisms of impaired diabetic wound healing remain enigmatic. A new non-apoptotic regulatory cellular death called Ferroptosis, is distinguished by iron-driven lipid peroxidation products accumulation along with insufficient antioxidant enzymes. A decline in antioxidant capacity, excess accumulation of peroxidation of iron and lipid have been identified in wound sites of streptozotocin-induced diabetes mellitus (DM) rats and elevated glucose (EG)-cultured macrophages. Additionally, sustained inflammation and increased inflammatory cytokines were observed in DM rats and HG-cultured macrophages. Importantly, ferrostatin-1 (Fer-1) is a ferroptosis suppressor treatment significantly ameliorated diabetes-related ferroptosis and inflammation. This treatment also enhanced cell proliferation and neovascularization, ultimately thereby accelerating diabetic wound healing. Meanwhile, our study demonstrated that an anti-ferroptotic and anti-inflammatory effects of Fer-1 were mediated through stimulation of nuclear erythroid-associated factor 2 (Nrf2). The current study may provide a new rationale for diabetic wound healing.