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Increasing evidence has shown that G-Rg2 exerts pharmacological effects such as neuroprotection, immune regulation, anti-inflammation and inhibition of tumor proliferation by reducing inflammatory response, blocking apoptotic cascade and regulating autophagic flow. In terms of mechanism of action, the diverse biological effects of G-Rg2 result from its background-dependent regulation of key intracellular signaling pathways such as AMPK, MAPK, NF-\u03baB and PI3K-AKT-mTOR, which are interconnected to form a complex regulatory network. This plasticity in pathway regulation confers bidirectional pharmacological properties of G-Rg2, which induces apoptosis through inhibition of the PI3K-AKT-mTOR pathway in MCF-7 breast cancer cells, whereas it activates the same pathway to promote cell survival in cardiomyocytes and neurons under ischemic conditions. Metabolomics and multiomics studies in animal models suggest that G-Rg2 regulates metabolic networks and multiple signaling pathways simultaneously in a complex disease environment, suggesting that G-Rg2 is most likely a network-level regulatory mode rather than a linear single-target action. The poor oral bioavailability, rapid systemic clearance, stereochemical complexity due to the 20(R)\/20(S) isomers, and insufficient long-term safety data of G-Rg2 have hindered its translation into clinical trials. Based on existing mechanism-related research on G-Rg2, this review proposes a network-based regulatory framework and offers specific suggestions to enhance the bioavailability and targeting of G-Rg2, providing actionable directions for its clinical translation.<\/jats:p>","DOI":"10.1142\/s0192415x26500631","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T07:13:03Z","timestamp":1786518783000},"page":"1695-1720","source":"Crossref","is-referenced-by-count":0,"title":["Context-Dependent Signaling Network of Ginsenoside Rg2: A Molecular Basis for Its Bidirectional Pharmacological Effects"],"prefix":"10.1142","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0561-5983","authenticated-orcid":false,"given":"Yu-Xi","family":"Gong","sequence":"first","affiliation":[{"name":"College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun 130118, P.\u00a0R. 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