A frog bioactive peptide suppresses inflammation by modulating autophagy for skin wound regeneration

Abstract Failure of inflammation resolution is a key driver of chronic skin wound pathogenesis, highlighting importance in wound healing. Although autophagy is known to regulate this process, it remains unclear whether amphibian-derived peptides exert their effects to facilitate regeneration of wounds through autophagy. Here, we identified OL-RA11, a previously unreported autophagy-regulatory peptide from Odorrana livida , which exhibits potent therapeutic effects on skin wounds. Mechanistically, OL-RA11 promoted wound healing through a dual cell-type-specific mechanism. During the early inflammatory stage, OL-RA11 enhanced autophagy in macrophages, which in turn induced M2 polarization and suppressed pro-inflammatory cytokine expression, thereby enabling inflammation resolution and facilitating the transition to the proliferative stage. In the proliferative phase, OL-RA11 directly activated the Wnt pathway in keratinocytes to enhance cell migration and promote re-epithelialization. Through this dual mechanism, autophagy and Wnt signaling acted independently in distinct cell types to coordinate inflammation resolution with regenerative activation, which ensured efficient, high-quality wound healing.