ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1655026
Mechanism of Swertiamarin and Novel Nitrogen-Containing Metabolites (R)-Gentiandiol and (S)-Gentiandiol in Treating Non-Alcoholic Fatty Liver Disease in Rats: An Untargeted Metabolomics Study based on UPLC-Q-TOF/MS
Provisionally accepted
Yidan Sun1Fuyan Cui2Shuhan Tang3Pengyu Li1Yaqi Xu1Hao Li1Yige Wang1Xintong Li1Minyue Zhang1Rong Ma1Xianna Li1Hongying Xu1
Ying Wang1Hailong Zhang4
Zhigang Wang1*- 1Heilongjiang University of Chinese Medicine, Harbin, China
- 2Shangqiu Third People's Hospital, Liangyuan District, Shangqiu, China, shangqiu, China
- 3Heilongjiang Hospital, Beijing Children's Hospital (Jiangnan Area, the Sixth Affiliated Hospital of Harbin Medical University), Youyi road 57, Harbin, China, harbin, China
- 4Xi'an Jiaotong University Health Science Center, Xi'an, China
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Swertiamarin, a predominant iridoid glycoside from hepatoprotective Swertia herbs, is biotransformed in vivo into nitrogen-containing metabolites (R)-gentiandiol and (S)-gentiandiol. These metabolites may be the real active hepatoprotective agents. A high-fat diet-fed rat model was treated for 12 weeks with swertiamarin, (R)-gentiandiol, (S)-gentiandiol and silybin, and the therapeutic effects on nonalcoholic fatty liver disease (NAFLD) were systematically evaluated through biochemical indices and histopathological observations. Swertiamarin and (R)-gentiandiol reversed high-fat diet-induced metabolic disturbances, reduced serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, low-density lipoprotein cholesterol and malondialdehyde, while elevated high-density lipoprotein cholesterol, superoxide dismutase and glutathione peroxidase. However, (S)- gentiandiol exhibited no efficacy. The differential biomarkers in the serum of high-fat diet-fed rats were determined and identified by the metabolomics method combined with multivariate analysis. The results of enrichment analysis showed that NAFLD could be improved by swertiamarin and (R)- gentiandiol by regulating the levels of 21 biomarkers, such as stearic acid, palmitic acid and PC (36:3). According to the pathway enrichment results, swertiamarin and (R)-gentiandiol had potent combined effects in regulating taurine and hypotaurine metabolism, arachidonic acid metabolism etc. This study is the first verification of the metabolite activity in the NAFLD model, and the dose-dependent effects of (R)-gentiandiol can be used to underscore its central role in swertiamarin's bioactivity. These findings offer valuable insights to clarify the pharmaceutical material for hepatoprotective effect of Swertia herbs.
Keywords: Swertiamarin1, (R)-Gentiandio2, (S)-Gentiandio3, Non-alcoholic fatty liver disease4, UPLC-Q-TOF/MS5, Chinese medicine monomers
Received: 27 Jun 2025; Accepted: 18 Aug 2025.
Copyright: © 2025 Sun, Cui, Tang, Li, Xu, Li, Wang, Li, Zhang, Ma, Li, Xu, Wang, Zhang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhigang Wang, Heilongjiang University of Chinese Medicine, Harbin, China
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