Targeting programmed cell death pathways in diabetic foot ulcers: Mechanisms and therapeutic strategies

Diabetic foot ulcers (DFU) represent a severe chronic complication of diabetes with increasing global prevalence. Approximately 75% of lower limb amputations are attributable to diabetic foot disease, and the 5-year mortality rate following amputation ranges from 53% to 100%. The pathogenesis of DFU involves multiple interacting factors, among which programmed cell death (PCD) plays a central role in impaired wound healing. Dysregulation of PCD modalities, including apoptosis, ferroptosis, pyroptosis, and autophagy, interacts with oxidative stress and immune dysfunction to create a pathological microenvironment that perpetuates tissue damage and delays repair. This narrative review is based on literature searches in PubMed, CNKI, and Web of Science up to 2026 using keywords related to DFU and PCD. It provides a comprehensive overview of the molecular mechanisms underlying different PCD pathways in DFU, explores their complex interrelationships and synergistic effects on wound healing, and discusses emerging therapeutic strategies targeting these cell death modalities. A deeper understanding of PCD regulatory networks may facilitate the development of novel therapeutic approaches and improve clinical outcomes for patients with DFU.