Cyclic HeptapeptideFZ1 Acts as an Integrin αvβ3Agonist to Facilitate Diabetic Skin Wound Healing by Enhancing Angiogenesis

Abstract Diabetic wound healing remains a persistent clinical challenge, necessitating the development of effective therapeutic agents and a deeper understanding of regulatory mechanisms. The cyclic heptapeptide FZ1, characterized by favorable biocompatibility, exhibited significantly greater efficacy than rh-bFGF and CyRL-QN15 in promoting cell proliferation and migration. In diabetic wound models, FZ1 markedly accelerated tissue regeneration and stimulated angiogenesis, as indicated by the upregulation of CD31 and α-SMA. Mechanistic investigations combining single-cell RNA sequencing, RNA interference, surface plasmon resonance, and molecular docking revealed that FZ1 directly bound to integrin αvβ3, activating FAK-dependent AKT and ERK1/2 signaling pathways to induce VEGFC expression. This signaling cascade enhanced endothelial cell proliferation, migration, and tube formation, collectively contributing to improved angiogenesis and wound closure. These findings identify FZ1 as the first peptide agonist targeting integrin αvβ3 with demonstrated pro-healing effects in diabetic wounds, representing a promising therapeutic candidate supported by defined molecular mechanisms.