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

Abstract

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 cells. Localized deferoxamine delivery stabilizes HIF-1α and restores angiogenic signaling in preclinical models; selenium supplementation restores GPX4-mediated lipid hydroperoxide clearance. Stimuli-responsive biomaterials coordinating DFO and antioxidant release in response to pathological ROS, MMP, and pH signatures represent a tractable delivery framework.ConclusionIron dyshomeostasis and ferroptosis constitute a therapeutically actionable axis in DFU pathology unaddressed by current standard of care. Large animal model validation and pharmacokinetic profiling in the DFU wound environment remain necessary before clinical translation.