Exploring the mechanisms of tetrahydrocurcumin in ameliorating nonalcoholic steatohepatitis based on network pharmacology and gut microbiota analysis in vivo and in vitro

Keyu Chen; Jianbo Wang; Shuang Luo; Yunyun Quan; Ping Wei; Jiali Fu; Jiali Ma; Yuying Yang; Yunten Liu; Zhichong Gao

doi:10.3389/fmicb.2025.1576221

Exploring the mechanisms of tetrahydrocurcumin in ameliorating nonalcoholic steatohepatitis based on network pharmacology and gut microbiota analysis in vivo and in vitro

Front Microbiol. 2025 Jun 17:16:1576221. doi: 10.3389/fmicb.2025.1576221. eCollection 2025.

Authors

Keyu Chen^{1

2

3}, Jianbo Wang^{1

4}, Shuang Luo^{4

5}, Yunyun Quan⁴, Ping Wei⁴, Jiali Fu⁵, Jiali Ma⁵, Yuying Yang⁶, Yunten Liu⁵, Zhichong Gao^{1

2

3}

Affiliations

¹ Pharmacology of Chinese Medicine, Shaanxi University of Chinese Medicine, Xianyang, China.
² Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, China.
³ Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China.
⁴ Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Xianyang, China.
⁵ College of Food and Biological Engineering, Chengdu University, Chengdu, China.
⁶ School of Pharmacy, Southwest Medical University, Luzhou, China.

Abstract

Background: The prevalence of nonalcoholic steatohepatitis (NASH) is increasing every year, and there are very few approved therapeutic agents globally, making the search for potentially targeted therapeutic agents important.

Aims: To investigate the anti-NASH effect of tetrahydrocurcumin (THC) and to further study the biological mechanism of THC anti-NASH from the perspective of intestinal flora.

Methods: Seven-week-old female male C57BL/6J mice were randomly divided into two batches of six groups: (1) control group, (2) model group, (3) positive control group, (4) THC low-dose group, (5) THC medium-dose group, and (6) THC high-dose group. The first batch of mice were fed with high-fat chow for 16 weeks in the rest of the groups except the control group; and the second batch of mice were fed with MCS chow in the control group, and MCS chow in the rest of the groups. MCD feed for 4 weeks. Serum, feces and liver tissues were collected separately. In addition, NASH cell model was established by using free fatty acids to induce AML-12 cells. Network pharmacology, molecular docking, high-throughput sequencing, protein blotting, and real-time fluorescence quantitative PCR were used to investigate the mechanism of THC against NASH.

Results: The intervention of THC improved the pathology of NASH, ameliorated liver injury, lowered lipid levels, and inhibited hepatic oxidative stress, inflammatory response and apoptosis compared with the high-fat feed-induced model group. In network pharmacology and animal experimental validation we found that THC reduced the expression of m RNA of PPARG, which may be the key to the improvement of NASH by THC. Intestinal flora analysis showed that THC altered the composition of the intestinal flora, which was characterized by a decrease in the proportion of Firmicutes/Bacteroidota.

Conclusion: The results of this study suggest that THC exerts anti-NASH effects by improving lipid levels, decreasing oxidative stress, attenuating inflammatory responses, and increasing the anti-apoptotic capacity of liver cells, and its efficacy is importantly associated with decreasing the expression of PPARG and improving the intestinal flora. THC is expected to be a potential therapeutic agent for NASH.

Keywords: 16S rRNA; intestinal flora imbalance; network pharmacology; nonalcoholic steatohepatitis; tetrahydrocurcumin.