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World J Gastroenterol. Jan 7, 2027; 33(1): 123034
Published online Jan 7, 2027. doi: 10.3748/wjg.123034
Mechanisms of Fuling Zexie decoction against metabolic dysfunction-associated steatotic liver disease: Integrative metabolomics, gut microbiota and serum pharmacochemistry
Peng-Quan Wang, Huan Yang, Yan-Mei Tang, Yu-Xuan Tao, Shao-Cong Han, Qi-Di Zhou, Jie Yu, Xing-Xin Yang
Peng-Quan Wang, Huan Yang, Yan-Mei Tang, Yu-Xuan Tao, Qi-Di Zhou, Jie Yu, Xing-Xin Yang, College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
Peng-Quan Wang, Huan Yang, Yan-Mei Tang, Yu-Xuan Tao, Shao-Cong Han, Qi-Di Zhou, Jie Yu, Xing-Xin Yang, Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
Shao-Cong Han, The First Clinical College, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
Co-first authors: Peng-Quan Wang and Huan Yang.
Co-corresponding authors: Jie Yu and Xing-Xin Yang.
Author contributions: Wang PQ, Yang H and Tang YM performed the experiments, acquired and analyzed data; Tao YX, Han SC and Zhou QD interpreted the data; Wang PQ and Yang H wrote the manuscript; Wang PQ and Yang H contributed equally to this work, and are co-first authors; Yang XX and Yu J designed and coordinated the study, and are co-corresponding authors; all authors have approved the final version of the article.
AI contribution statement: Portions of this manuscript were edited using Deepseek for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Supported by National Natural Science Foundation of China, No. 82560801 and No. 82104381; and Yunnan Fundamental Research Projects, No. 202505AF350032, No. 202407AB110018 and No. 202201AW070016.
Institutional review board statement: The study does not involve any human experiments.
Institutional animal care and use committee statement: Approval was obtained from the Ethical Committee on Animal Care and Experimentation of the Yunnan University of Chinese Medicine (approval No. R-062022135).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Corresponding author: Xing-Xin Yang, MD, Doctor, College of Pharmaceutical Science, Yunnan University of Chinese Medicine, No. 1076 Yuhua Road, Kunming 650500, Yunnan Province, China.
yxx78945@163.com
Received: May 7, 2026
Revised: June 23, 2026
Accepted: September 28, 2026
Published online: January 7, 2027
Processing time: 187 Days and 13.8 Hours
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) currently lacks specific therapeutic options. Fuling Zexie decoction (FZD) is a Chinese herbal formula that shows potential for treating MASLD, but its mechanism and active ingredients remain unclear.
AIM
To determine the mechanism and active ingredients of FZD against MASLD.
METHODS
Free fatty acid-stimulated steatotic HepG2 cells and high-fat diet-fed MASLD rats were used to assess the functionality of FZD. To investigate the mechanisms by which FZD affects endogenous metabolites and intestinal microbiota in rats, a combination of metabolomics and 16S rRNA sequencing was utilized. Serum pharmacochemistry-metabolomics integration identified FZD’s active ingredients and core targets, while molecular docking and cellular experimentation were utilized to validate the association of these ingredients and targets.
RESULTS
FZD ameliorated hepatic steatosis and hepatocellular injury in rats with MASLD, ameliorated serum and hepatic lipid levels, augmented antioxidant capacity, and mitigated inflammatory responses. Mechanistically, FZD restored 226 endogenous metabolites and regulated 17 metabolic pathways. This included reducing the Firmicutes/Bacteroidota ratio and diminishing the levels of potentially harmful microbes (Unclassified_f_Lachnospiraceae, Candidatus Saccharimonas, and Turicibacter). A total of 39 FZD-originated constituents were detected in the serum. Among these, 24 were recognized as key pharmacodynamic constituents that modulated 17 targets, 10 metabolic pathways, and 18 endogenous metabolites. The key pharmacodynamic compound group downregulated the expression of NOS2, MAOA, and MIF, thereby alleviating hepatic steatosis.
CONCLUSION
These results demonstrate that FZD alleviates MASLD by regulating 10 metabolic pathways, decreasing the abundance of Unclassified_f_Lachnospiraceae, Candidatus Saccharimonas, and Turicibacter, and normalizing 18 endogenous metabolite levels, which may be primarily attributed to the 24 FZD-derived active ingredients.
Core Tip: This study employed an integrative strategy combining metabolomics, gut microbiome profiling, and serum pharmacochemical analysis to elucidate the therapeutic effects of Fuling Zexie decoction on metabolic dysfunction associated with steatotic liver disease. Fuling Zexie decoction normalized 226 metabolites and 17 pathways in rats, while also reducing the Firmicutes/Bacteroidota ratio and the abundance of three pathogenic bacteria. Among 39 serum-derived components, 24 key components regulated 17 targets, 10 pathways, and 18 metabolites, and downregulated nitric oxide synthase 2, monoamine oxidase A, and macrophage migration inhibitory factor to alleviate hepatic steatosis.
