Clin Mol Hepatol > Volume 30(3); 2024 > Article
Clinical and Molecular Hepatology 2024;30(3): 449-467.
doi: https://doi.org/10.3350/cmh.2024.0047
Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against metabolic dysfunction-associated steatotic liver disease
Yiyuan Zheng1, Lina Zhao2,3, Zhekun Xiong4, Chaoyuan Huang5,6, Qiuhong Yong3,7, Dan Fang8, Yugang Fu1, Simin Gu1, Chong Chen1, Jiacheng Li1, Yingying Zhu1, Jing Liu1, Fengbin Liu2,3 , Yong Li1
1Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
3Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
4Department of Spleen, Stomach and Hepatobiliary, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, China
5Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
6Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
7The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
8Medical Affairs Department, Ton-Bridge Medical Technology Co., Ltd., Zhuhai, China
Correspondence :  Fengbin Liu ,
Tel: +86-020-36591912, Fax: +86-020-36591912, Email: liufengbin163@163.com
Yong Li ,
Tel: +86-021-56639828, Fax: +86-021-56639828, Email: liyong@shutcm.edu.cn
Received: January 18, 2024  Revised: April 12, 2024   Accepted: April 15, 2024
*Yiyuan Zheng, Lina Zhao and Zhekun Xiong contributed equally to this work.
ABSTRACT
Background/Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD.
Methods
Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings.
Results
In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression.
Conclusions
Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.
KeyWords: Metabolic dysfunction-associated steatotic liver disease; Ursolic acid; Secreted phosphoprotein 1; Th17 cells

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