Abstract
<title>Abstract</title> <p> Background Cutaneous wound healing proceeds through a tightly regulated sequence of four phases. Disruption of this process, particularly prolonged inflammation, often leads to delayed repair and the development of chronic wounds. Materials and methods In this study, we focused on the Fejervarin (Fej) family peptides, which were isolated from the skin secretions of <italic>Fejervarya moodiei</italic> , <italic>Fejervarya multistriata</italic> , <italic>Hylarana cubitalis</italic> , and <italic>Duttaphrynus melanostictus</italic> . By integrating molecular cloning, in vitro cellular functional assays, animal models, molecular interaction studies, and multi-omics technologies, we established a research framework encompassing: molecular identification - druggability evaluation - <italic>in vivo</italic> efficacy - target validation - pathway analysis. Results In murine models of full-thickness wounds, Fej peptides exhibit regulatory efficacy during both the inflammatory and proliferative phases, achieving 99% re-epithelialization by day 12, compared to 91% with human epidermal growth factor (EGF) gel (REFOO®). Biophysical analyses revealed that Fej-1a and Fej-1b directly bind to the transforming growth factor-β receptor II (TGFBR2) with dissociation constants (Kd) of 0.387 µM and 5.78 µM, respectively. During the inflammatory phase, Fej-1a and Fej-1b modulate inflammatory responses through the TGF-β-activated kinase 1 - nuclear factor-kappa B (TAK1-NF-κB) axis, thereby suppressing M1 macrophage activation while promoting M2 polarization, which accelerates the transition to the proliferative phase of wound healing. Concurrently, these peptides enhance fibroblast migration and collagen deposition by activating the TGF-β/Smad2/3 signaling pathway. Notably, Fej peptides exhibit negligible hemolytic activity and no detectable cytotoxicity <italic>in vitro</italic> and <italic>in vivo</italic> , underscoring their biocompatibility for topical application. Conclusion Our findings elucidate a dual-functioning family of amphibian anionic octapeptides that effectively bridge immune resolution and tissue remodeling, highlighting promising prospects for the development of peptide-based therapeutics in wound healing. </p>