Ferroptosis and Iron Dyshomeostasis as Drivers of Wound Chronicity in Diabetic Foot Ulcers: Pathophysiological Mechanisms and Targeted Therapeutic Strategies

作者：Qin TH, Shen S, Aziz A, Kamarul T, Ling XW, Haseeb A, Zulkifli EM, Tan HL, Wang AY · 发表于：The international journal of lower extremity wounds · 年份：2026 · DOI：10.1177/15347346261476551

Backgrounddiabetic foot ulcers (DFUs) carry 5-year mortality rates of 50%-70% and recurrence rates of 65% at three to five years. Standard-of-care protocols fail to resolve wound chronicity in a substantial proportion of patients, reflecting incomplete understanding of the cellular mechanisms sustaining non-healing. This narrative review examines trace element dyshomeostasis as a mechanistically distinct driver of ferroptotic cell death across wound-bed cell populations and evaluates targeted therapeutic strategies within this framework.MethodsLiterature was identified through narrative searches of PubMed and Web of Science; emphasis was placed on DFU-relevant experimental models and clinical populations.ResultsLabile iron pool expansion, arising from hemolysis-derived Fe2+ release, vasa nervorum compromise, ferritinophagy dysregulation, and SASP-mediated ferroportin suppression, sustains iron-catalyzed lipid peroxidation across Schwann cells, endothelial cells, fibroblasts, and macrophages. Three upstream metabolic axes, comprising AGEs/RAGE-mediated SLC7A11 suppression, eNOS uncoupling with BH4 depletion, and macrophage iron overload-driven polarization arrest, collectively lower the ferroptotic threshold at the wound margin. AGE-induced ECM stiffening further impairs fibroblast antioxidant capacity via mechanotransduction, while impaired NCOA4-dependent ferritinophagy renders senescent fibroblasts ferroptosis-resistant, sustaining SASP-driven iron retention in neighboring ...