The pursuit of developing groundbreaking pro-regenerative therapies to expedite skin wound healing persists as a formidable challenge. Peptide RL-QN15, emerges as a highly promising candidate for the first pro-regenerative drug derived from amphibian skin, offering a glimmer of hope for innovative healing treatments. Yet, there is an urgent need for intensified research efforts to propel RL-QN15 from a molecular entity to a viable drug candidate, particularly in unraveling the mechanisms underlying its exceptional pro-healing efficacy. In the current research, our results revealed that RL-QN15 significantly enhanced the proliferation, migration, stemness, and epithelial-to-mesenchymal transition of human epidermal stem cells (hESCs) through direct binding to the membrane frizzled 8 (FZD8) receptor. This interaction triggers the downstream Wnt/β-catenin signaling pathway, leading to the up-regulation of target genes MYC and CCND1. Furthermore, RL-QN15 augmented the expression and secretion of matrix metalloproteinase-3, which degrades E-cadherin and activates the Wnt/β-catenin pathway, thereby amplifying RL-QN15's regulatory effects on hESCs. In summary, our findings have demonstrated that RL-QN15 modulated the functions of ESCs to accelerate skin wound regeneration via the FZD8/β-catenin axis. This research not only advances peptide RL-QN15 from a molecular entity to a drug candidate by shedding light on the mechanisms involved with regulation of ESCs functions, but also presents compelling evidence implicating FZD8 as a novel therapeutic target for skin wound regeneration.

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