Integrative Multi-omics and Machine Learning Reveal the Therapeutic Mechanisms of Juanyu-Xiaozhi Formula in Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatic Fibrosis via the AP-1/PPARγ/SCD1 Axis
image: This study demonstrates the therapeutic efficacy of JYXZF in a MASH diet-induced rat model and elucidates its lipid-lowering and antifibrotic mechanisms through an integrated strategy combining multi-omics analyses, machine learning-based target prioritization, and functional validation experiments. We further show that JYXZF reduces hepatic lipid accumulation and collagen deposition by attenuating AP-1-mediated transcriptional activation of PPARγ and its downstream effector SCD1. Regulation of this AP-1/PPARγ/SCD1 pathway may contribute to the protective effects of JYXZF against MASLD/MASH progression. These findings not only clarify the mechanisms underlying the effects of JYXZF but also provide a basis for developing multi-target therapeutic approaches for metabolic liver diseases based on TCM.
Credit: Huabao Liu, Yang Yang
Background and Aims
Despite the surging global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and related liver fibrosis, effective treatments remain limited. While the traditional Chinese medicine Juanyu-Xiaozhi Formula (JYXZF) is used against MASLD, its bioactive components and mechanisms are poorly understood. This study aimed to investigate the therapeutic effects of JYXZF and elucidate its underlying mechanisms of action.
Methods
The constituents of JYXZF were characterized using ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Its efficacy was evaluated in a rat model of metabolic dysfunction-associated steatohepatitis (MASH) induced by a high-fat/calorie diet with high-fructose/high-glucose water, utilizing serum biochemistry, histology, and glucose/insulin tolerance tests. Mechanistic validation was performed in free fatty acid-treated human hepatocellular carcinoma cell line HepG2 (HepG2) cells and HepG2/human hepatic stellate cell line LX-2 (LX-2) co-culture models using luciferase assays, chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), and activator protein 1 (AP-1) overexpression rescue experiments. The functional relevance of stearoyl-CoA desaturase 1 (SCD1) was further assessed in vivo through liver-targeted adeno-associated virus (AAV)-mediated Scd1 overexpression.
Results
Flavonoids were identified as the main bioactive constituents. JYXZF administration alleviated metabolic dysfunction, reduced hepatic lipid accumulation, and attenuated inflammation and fibrosis in MASH rats. Multi-omics integration and machine learning-assisted target prioritization identified lipid metabolic and inflammatory pathways. Among these pathways, we selected the AP-1/peroxisome proliferator-activated receptor gamma (PPARγ)/SCD1-related lipogenic pathway for functional validation. Target perturbation experiments supported the functional involvement of AP-1 in the regulation of the PPARγ/SCD1 pathway and its contribution to the anti-steatotic effects of JYXZF.
Conclusions
JYXZF alleviates MASLD-associated steatosis and fibrosis via the AP-1/PPARγ/SCD1-related lipogenic axis, demonstrating its therapeutic potential for MASLD/MASH and providing a mechanistic basis for future clinical applications.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2026-00106
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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