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

  • Br J Pharmacol. 2026 Aug;183(15):4471-4499. doi: 10.1111/bph.70471.
Xuzi Zhang  1  2 ,  Ningning Yang  3 ,  Zhixuan Chen  1  2 ,  Yifan Huang  4 ,  Yingying Huang  1  2 ,  Jingwei Shi  1  2  5 ,  Hengrui Xu  1  2 ,  Xuwei Zhu  1  2 ,  Weijie Xia  1  2 ,  Zhenglin Li  3 ,  Weiyang Gao  1  2 ,  Jianjun Qi  6 ,  Jian Xiao  1  3  5 ,  Kailiang Zhou  1  2  5
Affiliations
  • 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2. Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, China.
  • 3. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 4. The First Clinical Medical College (School of Information and Engineering), Wenzhou Medical University, Wenzhou, China.
  • 5. Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, China.
  • 6. Department of Laboratory Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
PMID: 42063339 DOI: 10.1111/bph.70471
Abstract

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.

Keywords
FoxO3; RGD‐Latcripin‐7A; autophagy; ischaemic flaps; oxidative stress; targeted delivery.
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