Potential therapeutic strategies targeting ferroptosis in chronic diabetic wounds

Chronic diabetic wounds, most commonly presenting as diabetic foot ulcers (DFUs), represent one of the most devastating complications of diabetes mellitus. They affect a large proportion of diabetic patients worldwide and are associated with elevated risks of non-traumatic lower limb amputation, high mortality, and substantial socioeconomic burden. Many affected patients fail to achieve complete wound closure following standard-of-care treatment, highlighting a critical unmet need for novel mechanism-driven therapeutic targets. Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by the lethal accumulation of lipid peroxides, has emerged in recent years as a key pathogenic mechanism underlying impaired diabetic wound repair. Ferroptosis is defined by glutathione depletion, intracellular iron overload, and unrestrained lipid peroxidation. This review synthesizes current evidence regarding the regulatory mechanisms of ferroptosis, with a particular focus on its detrimental effects on the four major wound-repair-associated cell populations involved in cutaneous wound healing. Furthermore, we delineate the pathological alterations in chronic diabetic wounds that sensitize cells to ferroptosis. Ferroptosis-related biomarkers that may have clinical utility for predicting wound healing prognosis and monitoring therapeutic responses were also evaluated. A central emphasis of this review is placed on emerging anti-ferroptotic therapeutic strategies for diabetic wounds, accompanied by a critical appraisal of their preclinical efficacy and translational potential. Finally, we discuss prevailing challenges in the field and propose future research directions to accelerate the clinical translation of ferroptosis-targeted therapies for chronic diabetic wounds.