A novel recombinant peptide, RGD-Latcripin-7A, targeting neovascularization in skin transplantation: Tissue regeneration and autophagy mechanism.

BACKGROUND: Flap transplantation is a key approach for soft tissue reconstruction, but distal ischaemic necrosis remains a major limitation. Intravenous drug administration is preferred for treating ischaemic flaps; however, insufficient local drug concentrations before vascular reconstruction often reduce its efficacy. To address this, we developed a novel recombinant protein, RGD-Latcripin-7A (R-L), by fusing the autophagy-activating, ischaemia-protective protein Latcripin-7A (L) to the angiogenesis-targeting peptide RGD. METHODS: R-L was synthesized via solid-phase peptide synthesis. Cytotoxicity was assessed with a CCK-8 assay, live/dead staining, histology and serum biochemical analysis. Endothelial cell migration and angiogenesis were evaluated via scratch and tube formation assays. In vivo efficacy and targeting were examined through flap survival analysis, laser Doppler imaging, histology and in vivo imaging system (IVIS) fluorescence imaging. Mechanistic studies were performed using RNA sequencing, Western blotting, immunofluorescence, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). RESULTS: R-L demonstrated excellent biocompatibility and significantly promoted endothelial migration and angiogenesis. Following intravenous injection, R-L selectively accumulated in neovascular regions, markedly improved flap survival, and suppressed pyroptosis and necroptosis by restoring autophagic flux and alleviating oxidative stress. Mechanistically, R-L interacted with integrin αvβ3 to regulate the Akt-FoxO3-TGFβ signalling pathway, and FoxO3 knockdown abolished these protective effects. CONCLUSION: The novel recombinant peptide RGD-Latcripin-7A effectively targeted endothelial neovasculature and protected ischaemic flaps by modulating FoxO3-mediated autophagy and redox homeostasis, highlighting the promising therapeutic potential of this peptide for clinical application.