Korean Red Ginseng attenuates glucocorticoid-induced skin barrier dysfunction via mineralocorticoid receptor modulation.

Background: The skin serves as a critical barrier that maintains physiological homeostasis while protecting the body from environmental insults. Glucocorticoids (GCs) are effective anti-inflammatory agents, but prolonged use can compromise skin barrier integrity. Mineralocorticoid receptors (MRs) play a key role in GC-induced skin barrier dysfunction, although cross-talk with glucocorticoid receptors (GRs). This study investigates the potential of Korean Red Ginseng (KRG) and its active component, 20(R)-ginsenoside Rg3 (Rg3(R)), in modulating MR-associated signaling and attenuate GC-induced skin barrier impairment. Methods: MR transcriptional activity was assessed using luciferase reporter assays. Expression of SIRT1 and filaggrin, key markers of skin barrier function, was evaluated by quantitative PCR and Western blotting. MR knockdown with siRNA was performed to confirm its regulatory role. Molecular docking simulations predicted potential interactions between Rg3(R) and the MR ligand-binding domain. Results: GC treatment enhanced MR activation, reducing SIRT1 and filaggrin levels and compromising barrier integrity. KRG, particularly Rg3(R), attenuated GC-induced MR transactivation and nuclear localization, restoring SIRT1 and filaggrin expression and preserving keratinocyte differentiation. MR knockdown corroborated the protective effect of MR-associated pathway modulation. Molecular docking suggested a plausible interaction between Rg3(R) and the MR through direct binding. Conclusion: This study elucidates the pivotal role of MR in mediating GC-induced skin barrier dysfunction and identifies Rg3(R) from KRG as a promising therapeutic candidate for restoring skin barrier integrity. The findings provide a mechanistic basis for targeting MR signaling in the development of novel interventions for GC-associated skin disorders.