Cheng Z, Lu YF, He YX, Wei W, Xie YX, Lv TS, Wei Y, Lou Y, Yu JY, Zhou XQ. Integrated serum metabolomics reveal molecular mechanism of Xietu Hemu prescription on metabolic dysfunction-associated steatotic liver disease-related obesity. World J Hepatol 2025; 17(12): 113660 [DOI: 10.4254/wjh.v17.i12.113660]
Corresponding Author of This Article
Xi-Qiao Zhou, PhD, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210029, Jiangsu Province, China. zhouxiqiao@njucm.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Dec 27, 2025; 17(12): 113660 Published online Dec 27, 2025. doi: 10.4254/wjh.v17.i12.113660
Integrated serum metabolomics reveal molecular mechanism of Xietu Hemu prescription on metabolic dysfunction-associated steatotic liver disease-related obesity
Zhe Cheng, Yi-Fan Lu, Yi-Xian He, Wei Wei, Yi-Xuan Xie, Tian-Su Lv, Yi Wei, Yan Lou, Jiang-Yi Yu, Xi-Qiao Zhou
Zhe Cheng, Yi-Fan Lu, Yi-Xian He, Wei Wei, Yi-Xuan Xie, Tian-Su Lv, Yi Wei, Yan Lou, Jiang-Yi Yu, Xi-Qiao Zhou, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
Co-first authors: Zhe Cheng and Yi-Fan Lu.
Co-corresponding authors: Jiang-Yi Yu and Xi-Qiao Zhou.
Author contributions: Cheng Z and Lu YF contribute equally to this study as co-first authors; Yu JY and Zhou XQ contribute equally to this study as co-corresponding authors; Cheng Z conducted the experiments and wrote the manuscript; Lu YF, He YX and Wei W performed the Network analyses; Xie YX, Lv TS, and Wei Y reviewed and edited the manuscript; Lou Y provided the laboratory and technical materials; Yu JY and Zhou XQ designed the study.
Supported by Jiangsu Postgraduate Research and Practice Innovation Programme, No. KYCX24_2242; Science and Technology Project of Jiangsu Provincial Hospital of Traditional Chinese Medicine, No. Y22002; and Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous Traditional Chinese Medicine Experts, No.[2021]7.
Institutional animal care and use committee statement: The animal research protocol for obtaining drug-containing serum was approved by the Animal Ethics Committee of Nanjing University of Chinese Medicine (Approval No. 202406A101).
Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that would appear to influence their judgment.
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: No datasets were generated or analysed during the current study.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xi-Qiao Zhou, PhD, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210029, Jiangsu Province, China. zhouxiqiao@njucm.edu.cn
Received: September 1, 2025 Revised: October 22, 2025 Accepted: November 21, 2025 Published online: December 27, 2025 Processing time: 117 Days and 5.3 Hours
Abstract
BACKGROUND
Xietu Hemu prescription (XHP), a Chinese patent formula, is optimized based on the theory of “phlegm-dampness” and has been clinically validated to effectively combat metabolic dysfunction-associated steatotic liver disease (MASLD). It notably reduces visceral fat and body mass index. However, the molecular mechanisms underlying its regulation of lipid metabolism homeostasis remain unexplored.
AIM
To elucidate the mechanisms by which XHP inhibits adipocyte differentiation and maintains lipid metabolism homeostasis.
METHODS
The therapeutic efficacy of XHP in metabolic-related disorders was analyzed using HepG2 cells and 3T3-L1 cells, along with transcriptomics to assess gene expression alterations during white adipogenesis. The primary metabolites of XHP were identified through ultra-performance liquid chromatography, and metabolic pathways were examined via serum metabolomics. Network analysis was employed to predict therapeutic targets. The accumulation of lipid droplets and the expression of associated proteins were confirmed using oil red O staining and Western blotting, respectively. Molecular docking was utilized to identify core targets and signaling pathways, which were substantiated through immunofluorescence and siRNA interference.
RESULTS
XHP-containing serum (XHPS) significantly inhibited the transformation of normal HepG2 cells into fatty liver cells. Concurrently, the treatment suppressed the differentiation of 3T3-L1 cells, reduced lipid droplet accumulation and total cholesterol/triglyceride levels, and downregulated the expression of PPARγ, C/EBPα, and FABP4. Through transcriptomics and network pharmacological intersectionality analyses, 24 core targets were identified, predominantly enriched in the AMPK signaling pathway. Molecular docking validated the strong binding affinity of XHP metabolites to targets such as leptin (-11.3 kcal/mol) and ADIPOQ (-9.4 kcal/mol). ELISA results indicated that XHPS augmented leptin autocrine secretion, thereby activating the AMPK signaling pathway (P < 0.05). Conversely, LEPR knockdown negated this effect (P < 0.05).
CONCLUSION
XHP effectively inhibits adipogenesis and enhances lipid metabolism homeostasis through the LEP/AMPK/PPARγ pathway, presenting a promising multi-target therapeutic strategy for MASLD by mitigating lipotoxicity.
Core Tip: Xietu Hemu prescription, a traditional Chinese medicine formula, ameliorates metabolic dysfunction-associated steatotic liver disease-related obesity by inhibiting adipogenesis. Integrating serum metabolomics, transcriptomics, and network analysis, this study identified the LEP/AMPK/PPARγ signaling axis as the central mechanism. The formula promotes leptin autocrine secretion, activates AMPK phosphorylation, and subsequently downregulates PPARγ and SREBPs, thereby reducing lipid accumulation and improving metabolic homeostasis, offering a novel multi-target therapeutic strategy.
