Cyclic Heptapeptide FZ1 Acts as an Integrin αvβ3 Agonist to Facilitate Diabetic Skin Wound Healing by Enhancing Angiogenesis

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.

糖尿病创面愈合仍是一项长期存在的临床难题，亟需开发高效治疗手段并深入阐明其调控机制。具有良好生物相容性的环七肽（cyclic heptapeptide）FZ1，在促进细胞增殖与迁移方面的功效显著优于重组人碱性成纤维细胞生长因子（rh-bFGF）与CyRL‑QN15。在糖尿病创面模型中，FZ1可显著加速组织再生并促血管生成，这一效应可通过CD31与α平滑肌肌动蛋白（α-SMA）的表达上调得以验证。结合单细胞RNA测序（single-cell RNA sequencing）、RNA干扰（RNA interference）、表面等离子体共振（surface plasmon resonance）与分子对接（molecular docking）的机制研究表明，FZ1可直接结合整合素αvβ3（integrin αvβ3），激活依赖于黏着斑激酶（focal adhesion kinase，FAK）的AKT与ERK1/2信号通路，进而诱导血管内皮生长因子C（VEGFC）的表达。该信号级联反应可增强内皮细胞的增殖、迁移与管腔形成能力，最终协同促进血管生成与创面闭合。本研究发现FZ1是首个靶向整合素αvβ3的肽类激动剂（peptide agonist），在糖尿病创面中展现出明确的促愈合效应，且其作用机制已得到清晰阐明，是一款极具潜力的治疗候选药物。