Ginsenoside Rb2 modulates the skin barrier by targeting Src to regulate PI3K/Akt signaling in HaCaT cells

Ginsenoside Rb2 (G-Rb2) is a protopanaxadiol-type saponin, which is primarily enriched in the stems, leaves, and berries. G-Rb2 exhibits multiple biological effects, mainly including anti-diabetic, anti-obesity, cardiovascular protection, and anti-virus activities. However, the mechanism by which G-Rb2 regulates skin health has not been clearly elucidated. In this study, RNA sequencing (RNA-seq) was employed to analyze gene expression profiles in HaCaT cells treated with G-Rb2. Based on the bioinformatic results, HaCaT cells were treated with different concentrations of G-Rb2, and several in vitro cellular experiments were conducted to investigate the underlying mechanisms by which G-Rb2 regulates skin health. To further clarify the interaction between G-Rb2 and Src, molecular modeling approaches including density functional theory (DFT) calculations, molecular docking, and molecular dynamics (MD) simulations were performed. The results demonstrated that G-Rb2 exerted a pronounced skin-protective effect by activating Src and regulating skin health via the downstream PI3K/Akt signaling pathway. DFT-derived electrostatic potential and frontier orbital analyses, molecular docking, and 100-ns MD simulations collectively supported a stable binding mode of G-Rb2 to Src. These findings highlighted the potential of G-Rb2 as a natural functional compound for supporting skin health and preventing skin-associated disorders.