Peptide RL‐QN15 Regulates Functions of Epidermal Stem Cells to Accelerate Skin Wound Regeneration via the FZD8/β‐Catenin Axis

ABSTRACT 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.