Mesenchymal stem cells (MSCs) are highly susceptible to senescence during in vitro expansion and culture, particularly under oxidative stress conditions, which severely limits their therapeutic efficacy and clinical application. Ginsenoside Rh2, a bioactive compound derived from Panax ginseng, has been reported to regulate mitochondrial function; however, its role in MSC senescence remains insufficiently explored.
On December 24, 2025, a research team from the Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine (Westlake University Medical School) published a study entitled “Ginsenoside Rh2 inhibits mesenchymal stem cell senescence by regulating mitochondrial and lysosomal function” in Stem Cell Research & Therapy.
The study demonstrated that Rh2 effectively suppresses MSC senescence by activating Sirtuin 1 (SIRT1). At the molecular level, SIRT1 regulates the Pink1/Parkin-mediated mitophagy pathway and inhibits the secretion of senescence-associated inflammatory cytokines, including interleukin-6 (IL-6) and interleukin-8 (IL-8). These findings provide novel mechanistic insights into the anti-senescent effects of Rh2 and highlight its potential application in improving MSC-based therapies.
Rh2 Attenuates Senescence-Associated Phenotypes in Mesenchymal Stem Cells
The researchers first evaluated the effects of ginsenoside Rh2 on senescence in mesenchymal stem cells. The results showed that Rh2 significantly reduced senescence-associated β-galactosidase (SA-β-gal) activity in senescent MSCs. In addition, Rh2 treatment reversed cell cycle arrest and markedly decreased the levels of pro-inflammatory cytokines as well as key senescence markers, including p21, p16, and p53. These findings indicate that Rh2 effectively alleviates multiple hallmarks of cellular senescence in MSCs.
Rh2 Restores Mitochondrial and Lysosomal Function in Senescent MSCs
The researchers further investigated the impact of Rh2 on mitochondrial morphology and function in senescent MSCs. The results revealed that Rh2 treatment significantly ameliorated mitochondrial dysfunction and reduced the metabolic shift toward glycolysis commonly observed in senescent cells.
Another characteristic feature of cellular senescence is the upregulation of lysosomal protein expression and an increase in lysosomal content. Notably, Rh2 treatment reversed these alterations, suggesting a restoration of lysosomal homeostasis in senescent MSCs.
SIRT1-Mediated Regulation of Mitophagy and Lysosomal Acidity Underlies the Anti-Senescent Effects of Rh2
Mechanistically, Rh2 suppressed the release of senescence-associated cytokines through the activation of SIRT1, thereby regulating mitophagy. In addition, Rh2 enhanced lysosomal acidity via SIRT1-dependent pathways. Rh2 treatment also reduced the secretion of senescence-associated cytokines and extracellular vesicles, effectively mitigating the progression of MSC senescence.
Conclusion
In summary, this study demonstrates that oxidative stress–induced senescence in mesenchymal stem cells leads to pronounced mitochondrial and lysosomal dysfunction. Importantly, the study is the first to reveal that the traditional Chinese medicine–derived monomer ginsenoside Rh2 can suppress senescent phenotypes by restoring mitochondrial and lysosomal function. These findings provide a novel mechanistic basis for the potential application of Rh2 in improving the quality and therapeutic efficacy of MSCs.
References
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Ginsenoside Rh2 inhibits mesenchymal stem cell senescence by regulating mitochondrial and lysosomal function.
Stem Cell Research & Therapy.
Available at: https://link.springer.com/article/10.1186/s13287-025-04741-4