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Targeting ferroptosis promotes diabetic wound healing via Nrf2 activation
Tongcai Wang1,2,3, Yin Zheng4,5, Jun Zhang4,5
1NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
Abstract:
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.
Insights
Diabetic wound healing is impaired by ferroptosis, a cell death pathway. Ferrostatin-1 treatment suppressed ferroptosis and inflammation, accelerating healing by boosting cell proliferation and neovascularization.
Area of Science:
- Biomedical Science
- Cell Biology
- Diabetology
Background:
- Diabetic wound healing impairment is a significant clinical issue, often leading to amputation.
- Hyperglycemia in diabetes promotes oxidative stress, iron overload, and chronic inflammation, hindering wound repair.
- The precise molecular mechanisms underlying impaired diabetic wound healing remain largely unknown.
Purpose of the Study:
- To investigate the role of ferroptosis, a novel cell death pathway, in impaired diabetic wound healing.
- To explore the therapeutic potential of ferroptosis inhibition in accelerating diabetic wound closure.
- To elucidate the underlying molecular mechanisms of ferroptosis inhibition in diabetic wounds.
Main Methods:
- Induction of diabetes mellitus in rats using streptozotocin and culture of macrophages with elevated glucose.
- Assessment of ferroptosis markers, oxidative stress, and inflammatory cytokine levels in diabetic rat wound sites and high glucose-cultured macrophages.
- Treatment with ferrostatin-1 (Fer-1), a ferroptosis suppressor, and evaluation of its effects on wound healing, cell proliferation, and neovascularization.
- Investigation of the role of nuclear erythroid-associated factor 2 (Nrf2) in mediating the effects of Fer-1.
Main Results:
- Diabetic rats and high glucose-cultured macrophages exhibited markers of ferroptosis, including iron accumulation and lipid peroxidation, along with increased inflammation.
- Ferrostatin-1 treatment significantly reduced ferroptosis and inflammation in diabetic wound sites.
- Fer-1 administration promoted cell proliferation and neovascularization, leading to accelerated diabetic wound healing.
- The anti-ferroptotic and anti-inflammatory effects of Fer-1 were found to be mediated by the stimulation of Nrf2.
Conclusions:
- Ferroptosis plays a critical role in the pathogenesis of impaired diabetic wound healing.
- Inhibition of ferroptosis using ferrostatin-1 represents a promising therapeutic strategy for accelerating diabetic wound closure.
- Targeting ferroptosis via Nrf2 activation offers a novel approach to managing diabetic complications affecting wound repair.
