Dual‐Targeting Oligopeptide‐215 Regulates Skin Barrier Homeostasis Through Concurrent Modulation of JAK – STAT and NF ‐ κB Signaling

Objective To evaluate Oligopeptide‐215, a biomimetic peptide engineered from amphibian skin secretions, for its dual capacity to restore skin barrier homeostasis by concurrently targeting physical barrier proteins and inflammatory pathways via JAK–STAT and NF‐κB modulation. Methods In vitro models used UVB‐damaged HaCaT keratinocytes, LPS‐stimulated RAW264.7 macrophages, and IL‐4/IL‐13‐stimulated HaCaT cells. Assays included cell viability (MTT), migration (scratch), adhesion, barrier proteins (FLG/LOR; ELISA/IF), signaling phosphoproteins (pJAK1/pTYK2/pSTAT3/pSTAT6/pNF‐κB; IF), and inflammatory mediators (NO/PGE₂/TNF‐α/IL‐6/IL‐1β; ELISA). Results Oligopeptide‐215 antagonizes IL‐13/IL‐4‐mediated JAK–STAT6/STAT3 signaling, thereby restoring expression of critical barrier proteins FLG and LOR. Additionally, it suppresses inflammatory responses by inhibiting NF‐κB‐dependent cytokine production. In UVB‐damaged keratinocytes, Oligopeptide‐215 promotes cellular repair through enhanced proliferation, adhesion, and migration. Conclusion These findings revealed an innovative repairing mechanism combining physical barrier with immunologic barrier, and established Oligopeptide‐215 as a potential skincare ingredient for skin barrier dysfunction.