Autophagy-Ferroptosis Interplay Network: Redefining Therapeutic Paradigms for Diabetic Wound Healing

Diabetic wounds are clinically challenging due to poor healing and the potential for amputation in advanced cases. The roles of autophagy and ferroptosis, two pivotal regulators of cell fate, in diabetic wound healing have drawn increasing attention. However, a comprehensive review synthesizing their crosstalk in this context is lacking. This review addresses a central paradox: within the diabetic wound microenvironment, autophagy can either inhibit or promote ferroptosis, depending on the context. Integration of current evidence reveals that this paradox arises from the intricate coupling of autophagy and ferroptosis at key molecular nodes, including the p62-Keap1-Nrf2 axis, the NCOA4-mediated ferritinophagy axis, and a lipid-peroxide-driven feedback loop. The diabetic milieu, characterized by hyperglycemia, oxidative stress, and chronic inflammation, systemically disrupts the balance of this interactive network. This results in a self-reinforcing pathological state that drives cellular death, prolongs inflammation, and hinders tissue repair. This network imbalance is considered a critical molecular foundation of impaired diabetic wound healing. Consequently, we argue that therapeutic strategies must undergo a paradigm shift from single-target interventions toward multi-target, spatiotemporally specific modulation of network nodes. We systematically evaluate integrated pharmacological, bioengineering, and biophysical approaches to achieve this goal. However, it is important to acknowledge that the proposed framework is predominantly based on preclinical evidence, and its clinical translation warrants further validation. Despite this limitation, the integrative framework presented herein deepens the understanding of diabetic wound pathophysiology and provides a theoretical foundation for precision therapy in diabetic wounds.