Peptide RL-QN15 Accelerates Skin Wound Regeneration by Activating FZD8/β-Catenin in Epidermal Stem Cells

Developing effective pro-regenerative therapies for skin wound healing remains a significant challenge, with current treatments often falling short in promoting robust and sustained regeneration. The complex wound microenvironment and issues like peptide degradation and rapid clearance limit the efficacy of many promising candidates. Peptide RL-QN15, derived from amphibian skin, shows potential as a novel pro-regenerative agent. However, its precise mechanisms of action, particularly how it modulates epidermal stem cell (ESC) functions, have been unclear, hindering its progression from a molecular entity to a viable drug candidate.

Researchers investigated RL-QN15's effects on human epidermal stem cells (hESCs) to elucidate its pro-healing efficacy and underlying mechanisms. They assessed hESC proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) in vitro. The study focused on identifying direct binding targets on the cell membrane and characterizing the downstream signaling pathways activated by RL-QN15, specifically examining the Wnt/β-catenin axis and its impact on target gene expression. They also analyzed the peptide's influence on matrix metalloproteinase-3 expression and secretion.

RL-QN15 significantly enhanced the proliferation, migration, stemness, and epithelial-to-mesenchymal transition of hESCs. This pro-regenerative effect was directly mediated by RL-QN15's binding to the membrane frizzled 8 (FZD8) receptor. This interaction subsequently triggered the downstream Wnt/β-catenin signaling pathway, leading to the notable up-regulation of target genes MYC and CCND1. Furthermore, RL-QN15 augmented the expression and secretion of matrix metalloproteinase-3, which plays a crucial role in degrading E-cadherin and further activating the Wnt/β-catenin pathway. This amplification mechanism enhanced RL-QN15's regulatory effects on hESCs.