Ginsenoside Rg1 alleviates chronic stress-induced depression in rats by targeting Cx43-YAP axis

Although significant progress has been made in the development of antidepressants, a large subpopulation of individuals remains unresponsive to existing treatments. Ginsenoside Rg1 (Rg1), a natural compound with well-defined antidepressant effects and low-cost administrations, holds therapeutic promise but requires mechanistic elucidation for clinical translation. Based on our previous finding that Rg1 rescued astrocytic connexin43 (Cx43) downregulation in depression models, we investigated its brain-wide effects and molecular mechanisms in chronic unpredictable stress (CUS)-induced rats. Male rats subjected to CUS received Rg1 (40 mg· kg^-1 ·d^-1, i.g.) for 8 weeks. Multimodal neuroimaging (fMRI and PET/CT) revealed that Rg1 restored functional connectivity and ameliorated neuroinflammation in CUS rats, with the prelimbic area identified as a critical target region. Through integrated proteomic profiling, molecular docking, and surface plasmon resonance analyses, we pinpointed Cx43-mediated gap junction as the primary target underlying Rg1's therapeutic action. Mechanistically, we showed that Yes-associated protein (YAP), the primary effector of the Hippo pathway, was translocated into the nucleus to promote the expression of specific genes including those involved in inflammation. Notably, we demonstrated that Rg1 potentiated the Cx43-YAP interaction in the cytoplasm and restricted YAP nuclear translocation activity. The degradation of Cx43 and potentiation of YAP nuclear translocation might represent a novel mechanism for the pathogenesis of depression. Specific blockade of Cx43-based gap junctions, knockdown of Cx43 expression in primary cultured astrocytes, and conditional knockout of astrocytic Cx43 in mice promoted YAP nuclear translocation and retarded the antidepressant effects of Rg1. Accordingly, the Cx43-YAP connection may represent a potential therapeutic target for the antidepressant mechanism of Rg1.