Research Progress on the Role and Mechanisms of Ferroptosis in Diabetic Wound Repair
Summary: This review explores ferroptosis—an iron-dependent cell death driven by lipid peroxidation and antioxidant dysregulation—as a key contributor to delayed diabetic wound healing, particularly in diabetic foot ulcers (DFUs). High-glucose environments exacerbate ferroptosis in repair cells (macrophages, fibroblasts, endothelial cells, keratinocytes), disrupting inflammation, angiogenesis, and re-epithelialization. Mechanisms include Fenton reactions from Fe²⁺, PUFA peroxidation via ACSL4/lipoxygenases, and impaired GPX4/GSH defenses. Therapeutic inhibition with Ferrostatin-1, deferoxamine, or natural compounds (resveratrol, PRP, MSC-EVs) reduces ferroptosis, enhancing granulation and closure in diabetic models, while activation targets bacterial biofilms. The review calls for clinical trials on ferroptosis biomarkers and multimodal therapies to overcome DFU chronicity.
Key Highlights:
- Ferroptosis disrupts diabetic healing via iron overload, ROS, and GPX4 inhibition; key in DFU refractory cases.
- Cell-specific effects: Macrophages shift to M1; fibroblasts impair ECM; endothelial cells reduce VEGF; keratinocytes delay migration.
- Inhibitors like Ferrostatin-1 or 4-octyl itaconate accelerate closure 40-60% in diabetic rats by boosting Nrf2/GPX4.
- Bacterial role: Ferroptosis-sensitive pathogens (E. coli) cleared by iron-loaded hydrogels; aids infection control.
- Implications: Ferroptosis as DFU biomarker; training for multimodal (topical/systemic) interventions needed.
Keywords: ferroptosis, diabetic wound, lipid peroxidation, GPX4, DFU therapy