Role of Ferroptosis in Diabetic Foot Ulcers: Pathophysiological Mechanisms,  Biomarkers, and Therapeutic Potencies

Abstract

Diabetic foot ulcer (DFU) is one of the major complications of diabetes mellitus and often results in persistent non-healing lesions, infections, and amputations. Recently, an iron-dependent form of programmed cell death, ferroptosis, has been shown to have an essential role in the poor regeneration of DFUs. This mini-review aims to study the role of ferroptosis in the pathophysiology of diabetic wounds, clinical biomarkers, and potential treatments by targeting ferroptotic pathways. Hence, PubMed-indexed studies on ferroptosis in relation to diabetic wound healing, including in vitro, animal, and clinical studies, were systematically reviewed. The research was evaluated based on molecular mechanisms, biomarkers, and preclinical and clinical evidence. Ferroptosis inhibits wound healing by promoting lipid peroxidation, oxidative stress, and cell death in fibroblasts, keratinocytes, and endothelial cells. Wound severity and healing are associated with tissue and circulation biomarkers such as Glutathione Peroxidase 4 (GPX4), Solute Carrier Family 7 Member 11 (SLC7A11), Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), Malondialdehyde (MDA), and 4-Hydroxynonenal (4-HNE). Several treatments, including small-molecule ferroptosis inhibitors, iron chelators, and extracellular vesicles from mesenchymal stem cells, have demonstrated therapeutic benefits in preclinical studies (in vitro and animal models) and early-phase clinical assessments, although no randomized controlled trials are currently available. Inhibition of ferroptosis is a promising and rational therapeutic approach to improve DFU healing. It is essential to normalize these biomarkers, optimize therapeutic regimens, and perform extensive, robust clinical trials to translate the preclinical findings for chronic diabetic wounds into effective patient treatments.