Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds

Diabetic wounds are a severe complication of diabetes, which can lead to amputation or even mortality in severe cases. While normal wound healing consists of four phases: hemostasis, inflammation, proliferation, and remodeling, diabetic wounds tend to become chronic and refractory primarily due to a prolonged inflammatory phase. In diabetic wounds, insufficient synthesis and release of endogenous calcitonin gene-related peptide (CGRP) is a critical upstream mechanism underlying the disrupted neuro-immune communication, the persistent inflammation, and the arrested wound healing process. In contrast to pure skin defect wounds, where CGRP is rapidly upregulated after injury, CGRP remains persistently low in diabetic wound tissue, consequently failing to drive macrophage polarization towards the M2 phenotype or promote vascular maturation and collagen fiber deposition in the later phase of inflammation. In the early inflammatory phase, CGRP exerts pro-inflammatory effects by enhancing angiogenesis and modulating macrophage polarization. In the late inflammatory phase, CGRP upregulates thrombospondin-1, promotes neutrophil apoptosis and phagocytic clearance, thereby inhibiting excessive inflammatory response and shifting the wound microenvironment from a pro-inflammatory state to a pro-reparative state. Restoring CGRP signaling reconstructs the neuroimmunomodulation axis and improves wound repair while relieving diabetic neuropathic pain. Engineered CGRP combined with intelligent delivery systems offers promising prospects for diabetic wound therapy. However, large-scale clinical trials are still required to validate its clinical efficacy and safety. This paper systematically analyzes the mechanisms and application strategies of CGRP in facilitating diabetic wound repair, which can provide a theoretical basis and innovative strategies for clinical management.