Ma Jiahui, Bai Xue, Duan Zhiguang, Fu Rongzhan, Zeng Wen, Li Yang, Guan Zhenghui, Zhu Chenhui
Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710127, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710127, China; Xi'an Synthetic Biology Technology and Biomaterials International Science and Technology Cooperation Base, School of Chemical Engineering, Northwest University, Xi'an 710127, China.
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Life Sci. 2025 Oct 1;378:123818. doi: 10.1016/j.lfs.2025.123818. Epub 2025 Jun 20.
Ginsenoside Rg5 (Rg5) has been certified to have superior activity in relieving the symptoms of non-alcoholic steatohepatitis (NASH). Nevertheless, the potential application of Rg5 is limited owing to its instability during storage. This study aims to enhance the stability of Rg5 through structural modification and evaluate its efficacy in treating NASH.
The modification involved the hydrogenation of the double bonds at C-20 (22) and C-24 (25) to form 2H-ginsenoside Rg5 (2HRg5). We used spectroscopic techniques including H-NMR, C-NMR, and high-resolution mass spectrometry to characterize the structure of 2HRg5. In addition, we used High-performance liquid chromatography (HPLC) to study the stability changes through stability experiments at 25 or 60°C for 25 days. We created NASH models in vitro and in vivo and used transcriptomics, molecular docking, and molecular dynamics simulations to examine the impact of 2HRg5 on NASH lipid accumulation, fibrosis, and liver inflammation.
After 25 days at 60°C, 2HRg5 retained 82.7% of the active content compared to 9.4% for Rg5, with superior reduction in lipid accumulation, inflammation, and fibrosis in NASH mice. 2HRg5 inhibits the STING-TBK1-IRF3 pathway and reduces type I interferon release and inflammation. Moreover, the high binding efficiency and remarkable system stability between 2HRg5 and STING further support our findings.
2HRg5 provides improved storage stability and efficacy, making it a promising therapeutic candidate for NASH.
人参皂苷Rg5（Rg5）已被证实具有缓解非酒精性脂肪性肝炎（NASH）症状的卓越活性。然而，由于其在储存过程中的不稳定性，Rg5的潜在应用受到限制。本研究旨在通过结构修饰提高Rg5的稳定性，并评估其治疗NASH的疗效。
修饰过程包括将C-20（22）和C-24（25）处的双键氢化，以形成2H-人参皂苷Rg5（2HRg5）。我们使用了包括氢核磁共振（H-NMR）、碳核磁共振（C-NMR）和高分辨率质谱在内的光谱技术来表征2HRg5的结构。此外，我们通过在25或60°C下进行25天的稳定性实验，使用高效液相色谱（HPLC）来研究稳定性变化。我们在体外和体内建立了NASH模型，并使用转录组学、分子对接和分子动力学模拟来研究2HRg5对NASH脂质积累、纤维化和肝脏炎症的影响。
在60°C下放置25天后，2HRg5保留了82.7%的活性成分，而Rg5仅保留了9.4%，2HRg5在NASH小鼠中对脂质积累、炎症和纤维化的减少效果更佳。2HRg5抑制STING-TBK1-IRF3通路，并减少I型干扰素释放和炎症。此外，2HRg5与STING之间的高结合效率和显著的系统稳定性进一步支持了我们的发现。
2HRg5具有更好的储存稳定性和疗效，使其成为NASH有前景的治疗候选药物。
