Alisol B ameliorated metabolic dysfunction-associated steatotic liver disease via regulating purine metabolism and restoring the gut microbiota disorders

Lin Yiyou; Zhang Congcong; Ren Guilin; Qiu Jiannan; Fu Yilong; Liu Fucai; Liu Qingsheng; Yu Zhiling; Chen Lin; Dou Xiaobing

doi:10.1016/j.phymed.2025.156992

Alisol B ameliorated metabolic dysfunction-associated steatotic liver disease via regulating purine metabolism and restoring the gut microbiota disorders

Phytomedicine. 2025 Jun 22:145:156992. doi: 10.1016/j.phymed.2025.156992. Online ahead of print.

Authors

Lin Yiyou¹, Zhang Congcong¹, Ren Guilin¹, Qiu Jiannan¹, Fu Yilong¹, Liu Fucai¹, Liu Qingsheng², Yu Zhiling³, Chen Lin⁴, Dou Xiaobing⁵

Affiliations

¹ School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China; Zhejiang-Hong Kong Joint Laboratory of Liver and Spleen Simultaneous Treatment in Traditional Chinese Medicine, Zhejiang, PR China.
² Hangzhou Third People's Hospital, Hangzhou, Zhejiang, PR China.
³ Zhejiang-Hong Kong Joint Laboratory of Liver and Spleen Simultaneous Treatment in Traditional Chinese Medicine, Zhejiang, PR China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
⁴ School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China. Electronic address: chenlin@zcmu.edu.cn.
⁵ School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China. Electronic address: xbdou77@gmail.com.

PMID: 40582207
DOI: 10.1016/j.phymed.2025.156992

Abstract

Background: Alisol B (AB) has been demonstrated to be a potential lead compound in improving obesity-related metabolic disorders. Nevertheless, the effects and mechanisms of AB on Metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear.

Purpose: This study aimed to investigate the improvement of AB on MASLD and explore the intricate mechanism involving gut microbiota and liver metabolism.

Materials and methods: The MASLD mice model was established by feeding a high-fat diet and oral treatment with AB. The effects of AB on lipid metabolism in MASLD were initially measured. Subsequently, 16S rRNA gene sequencing, untargeted metabolomics combined with network pharmacology analysis was used to unveil the potential mechanism of AB on MASLD. A series of molecular biology experiments was conducted to confirm the results of the multi-omics analysis and to elucidate the key mechanism.

Results: AB attenuated liver steatosis and improved liver injury in MASLD mice. AB treatment improved the diversity of gut microbiota and increased the abundance of Akkermansia, Escherichia-Shigella, and Muribaculu in MASLD mice. Based on correlation analysis between differential intestinal microbiota and metabolites, metabolites involving sodium oleate, helleolate acetate 3-acetate and oxaminate were identified as key metabolites. In addition, integrating metabolomics and network pharmacology showed that AB alleviated MASLD by regulating the purine metabolism pathway and de novo fatty acid biosynthesis. Then, we focused on the role of purine metabolism in the treatment of MASLD by AB. Notably, AB inhibited the urine acid level in serum and liver of MASLD mice and hepatic XO activity and expression. AB markedly reduced the hypoxanthine and allantoin levels, increased the inosine level in the livers of MASLD mice, indicating that AB significantly reversed the dysfunction of hepatic purine metabolism in MASLD. Moreover, Molecular docking and surface plasmon resonance (SPR) results demonstrated that AB directly binds to XO. Overexpressing XO abolished the effect of AB in lipid accumulations in AML-12 cells. AB may alleviate MASLD by directly targeting XO to inhibit purine metabolism disorders in the liver.

Conclusion: Our results demonstrate that AB treatment attenuates HFD-induced MASLD through dual mechanisms involving gut microbiota modulation and restoration of hepatic metabolic homeostasis. Comprehensive mechanistic analysis revealed that AB ameliorates hepatic steatosis and corrects purine metabolism dysregulation in MASLD pathogenesis through specific inhibition of XO. These findings provide novel mechanistic insights into the hepatoprotective properties of AB and establish its therapeutic potential for MASLD intervention.

Keywords: Alisol B; Gut microbiota; Metabolic dysfunction-associated steatotic liver disease; Metabolomics; Purine metabolism.