Ginsenoside Compound K activates EGFR to enhance the skin barrier- and moisturization-related molecules

Ginseng is a well-known tonic herb used for thousands of years. Ginsenosides, the major components of ginseng, exhibit various biological functions. Among these, their roles in skin health attract increasing attention. Compound K (C-K), a secondary metabolite of ginsenosides, has been reported to enhance skin moisturization and melanin secretion. However, the upstream signaling pathways have not been clearly clarified.

Cell viability assay assessed the cytotoxicity of C-K, and luciferase reporter gene assay screened potential signaling pathways. Quantitative polymerase chain reaction (qPCR) evaluated the mRNA levels of skin barrier- and hydration-related genes. Western blot and Cellular Thermal Shift Assay (CETSA) confirmed the signalings and targets, while molecular docking predicted residues.

Cell viability assays showed C-K exhibited no significant cytotoxicity in HEK293T at 10 μM and in HaCaT cells at 3 μM. C-K also promoted the mRNA expressions of FLG, HAS-2, AQP3, loricrin, and involucrin. Luciferase assay and qPCR treated with inhibitors revealed that C-K activated mitogen-activated protein kinases (MAPKs), nuclear factor kappa-B (NF-κB), and cyclic AMP response element-binding protein (CREB) signaling pathways, which were confirmed by western blotting. CETSA further identified epidermal growth factor receptor (EGFR) as a potential target of C-K, and molecular docking showed putative interactions between C-K and the residues of EGFR.

Taken together, C-K exhibited potent effects in enhancing skin barrier and hydration by phosphorylated EGFR at Tyr1173, thereby activating MAPKs, NF-κB, and CREB signaling cascades. These findings provide fundamental evidence supporting the use of C-K as a cosmetic ingredient and a promising option for skin protection.