The role and mechanism by which micropeptide WHPP promote refractory wound healing

Full-thickness skin wounds present significant clinical challenges, highlighting an urgent need for accelerated healing strategies. Recent studies have elucidated the involvement of long non-coding RNAs (lncRNAs) in skin wound healing processes, whereby certain lncRNAs regulate key biological functions. Among emerging regulatory factors, small open reading frames (smORFs) within lncRNAs, which encode polypeptides termed small peptides (SEPs), have been implicated in the pathogenesis of various diseases, including tumors and metabolic disorders. Notably, the role of SEPs in wound healing remains unexplored, necessitating further investigation. This study aims to elucidate the function of an SEP, denoted as WHPP (Wound Healing Promoting Peptide), which is encoded by the lncRNA MSTRG22314.1, in the context of skin wound healing.

We employed in vitro assays using primary keratinocytes to evaluate the effects of WHPP on cell behavior relevant to wound healing, specifically assessing cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). In vivo analyses involved the administration of WHPP in a rat model of skin injury to assess its therapeutic efficacy on wound closure.

Our findings indicate that WHPP significantly enhances the proliferation and migration of basal keratinocytes while facilitating EMT through the activation of Twist1 protein. Moreover, in vivo experiments revealed that WHPP administration markedly accelerated skin wound healing in rats, corroborated by evidence that WHPP inhibits the degradation of Twist1 protein in keratinocytes.

This study represents the first report on the involvement of SEPs, specifically WHPP, in the regulatory mechanisms of wound healing. We suggest that WHPP treatment may provide an innovative therapeutic avenue for patients with chronic and difficult-to-heal wounds. Future research is warranted to delineate the comprehensive molecular pathways influenced by WHPP and to explore its potential applications in clinical settings.