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

Acta Pharmacologica Sinica volume 46, pages 1877–1891 (2025)Cite this article

Abstract

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.

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Fig. 1: Rg1 attenuated depression-like behaviors in CUS rats.
Fig. 2: Rg1 improved resting-state FC in CUS rats.
Fig. 3: Rg1 reduced the degree of CUS-induced neuroinflammation in the PrL.
Fig. 4: Rg1 targeted Cx43-GJs to exert antidepressant effects.
Fig. 5: Rg1 restored GJ function and Cx43 expression after CUS injury.
Fig. 6: Rg1 inhibited YAP nuclear translocation by Cx43-GJs after stress stimulation.
Fig. 7: Cx43-GJ dysfunction accelerated YAP nuclear translocation.
Fig. 8: Rg1 regulated YAP nuclear translocation through Cx43.
Fig. 9: Rg1 targeted astrocytic Cx43-YAP interaction to mitigate depression.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82130109, U2202214), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-020), Hunan University of Chinese Medicine First-Class Discipline Construction Project of Chinese Material Medica (201803).

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Authors and Affiliations

  1. School of Pharmacy, Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, China

    Hui-qin Wang, Qi-di Ai, Song-wei Yang, Qian Yan, Yan-tao Yang & Nai-hong Chen

  2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Hui-qin Wang, Xue-ying Yang, Ai-ping Chen, Xu Yan, Zhao Zhang, Shi-feng Chu, Zhen-zhen Wang & Nai-hong Chen

  3. Xinjiang Institute of Materia Medica, Urumqi, 830002, China

    Rui-fang Zheng, Jian-guo Xing & Nai-hong Chen

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  1. Hui-qin Wang
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Contributions

NHC and HQW conceived and designed this study. HQW performed experiments, analyzed data, and wrote the manuscript. RFZ, QDA, SWY, XYY, APC, and QY performed experiments and verified data. XY, ZZ, JGX, and SFC provided materials and administrated project. ZZW, YTY, and NHC revised the manuscript and were responsible for funding investigation, data curation, and supervision. All the authors have read and approved the final version of the manuscript.

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Correspondence to Zhen-zhen Wang, Yan-tao Yang or Nai-hong Chen.

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Wang, Hq., Zheng, Rf., Ai, Qd. et al. Ginsenoside Rg1 alleviates chronic stress-induced depression in rats by targeting Cx43-YAP axis. Acta Pharmacol Sin 46, 1877–1891 (2025). https://doi.org/10.1038/s41401-025-01515-9

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