Molecular insights into diabetic wound healing: Focus on Wnt/β-catenin and MAPK/ERK signaling pathways

Diabetic wounds manifest significant clinical challenge with approximately 50–70 % reporting non-traumatic lower limb amputations annually. This review examines the intricate relationship between impaired wound healing in diabetes mellitus and two crucial signaling pathways: Wnt/β-catenin and MAPK/ERK. Chronic hyperglycemia in diabetes mellitus leads to peripheral neuropathy, vascular dysfunction, and compromised immune responses, resulting in delayed wound healing. The Wnt/β-catenin pathway, which is essential for cellular proliferation, differentiation, and tissue homeostasis, shows altered activity in diabetic wounds, particularly through decreased R-spondin 3 protein expression. Similarly, the MAPK/ERK pathway, which regulates cellular proliferation and differentiation through hierarchical kinase cascades, exhibits dysregulation under diabetic conditions. This review describes the current understanding of normal wound healing processes, diabetic wound pathophysiology, and the molecular mechanisms of both signaling pathways. Evidence suggests that targeting these pathways, either individually or synergistically offer promising therapeutic approaches for diabetic wound management. Future directions include, developing targeted delivery systems, exploring pathway cross-talk, and investigating dual-pathway modulators to enhance wound healing outcomes in diabetic patients. This comprehensive analysis provides insights into potential therapeutic strategies and emphasizes the necessity of research in this crucial area of diabetes treatment. (Graphical Abstract)