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Peptide RL\u2010QN15, emerges as a highly promising candidate for the first pro\u2010regenerative 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\u2010QN15 from a molecular entity to a viable drug candidate, particularly in unraveling the mechanisms underlying its exceptional pro\u2010healing efficacy. In the current research, our results revealed that RL\u2010QN15 significantly enhanced the proliferation, migration, stemness, and epithelial\u2010to\u2010mesenchymal transition of human epidermal stem cells (hESCs) through direct binding to the membrane frizzled 8 (FZD8) receptor. This interaction triggers the downstream Wnt\/\u03b2\u2010catenin signaling pathway, leading to the up\u2010regulation of target genes MYC and CCND1. Furthermore, RL\u2010QN15 augmented the expression and secretion of matrix metalloproteinase\u20103, which degrades E\u2010cadherin and activates the Wnt\/\u03b2\u2010catenin pathway, thereby amplifying RL\u2010QN15's regulatory effects on hESCs. In summary, our findings have demonstrated that RL\u2010QN15 modulated the functions of ESCs to accelerate skin wound regeneration via the FZD8\/\u03b2\u2010catenin axis. This research not only advances peptide RL\u2010QN15 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.<\/jats:p>","DOI":"10.1002\/exp.20240090","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T01:44:28Z","timestamp":1749433468000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Peptide RL\u2010QN15 Regulates Functions of Epidermal Stem Cells to Accelerate Skin Wound Regeneration via the FZD8\/\u03b2\u2010Catenin Axis"],"prefix":"10.1002","volume":"6","author":[{"given":"Yuansheng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anatomy and Histology &amp; Embryology, Faculty of Basic Medical Science Kunming Medical University  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuye","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology &amp; 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