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Background <p>Liver fibrosis, a common pathological progression in chronic liver diseases, can lead to irreversible cirrhosis and hepatocellular carcinoma if untreated. Gurigumu-13, a traditional herbal formulation, has demonstrated promising protective and therapeutic effects against liver fibrosis in clinical settings. However, its underlying antifibrotic mechanisms remain unclear.</p> Methods <p>A rat model of hepatic fibrosis was induced via intraperitoneal injection of dimethylnitrosamine (DMN). Rats were treated with high, medium, or low doses of Gurigumu-13. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) were measured to evaluate liver function. Hepatic hydroxyproline (Hyp), laminin (LN), alpha-smooth muscle actin (α-SMA), and type IV collagen (Col-IV) were measured to assess liver function. Liver tissues were subjected to hematoxylin–eosin (HE), Masson, and Sirius Red staining to evaluate histopathological changes and collagen deposition. The expression of alpha-smooth muscle actin (α-SMA) and type I collagen (Col-I) in liver tissue was analyzed by immunohistochemistry (IHC) and western blot (WB). Metabolomics analysis was performed on liver samples, followed by multivariate statistical analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, network pharmacology prediction, and molecular docking to explore differential metabolites, enriched metabolic pathways, potential target genes, and key ligand-receptor interactions.</p> Results <p>Gurigumu-13 significantly improved liver function by reducing serum ALT, AST, and ALP levels, TBIL, Hyp, LN, α-SMA, and Col-IV and alleviating hepatic histological damage in a dose-dependent manner (H-G13 vs. DMN, <i>p</i> &lt; 0.001). It also downregulated the expression of fibrosis-related markers α-SMA and Col-I (H-G13 vs. DMN, <i>p</i> &lt; 0001). A total of 227 differential metabolites were identified between the DMN and H-G13 groups, showing significant alterations in lipid, amino acid, and organic acid metabolism. KEGG pathway analysis revealed enrichment in pathways such as 5 significantly enriched metabolic pathways include "L-Tyrosine", "2-Hydroxycinnamic acid", "ortho-Hydroxyphenylacetic acid", "L-3-Phenyllactic acid", "N-Acetyl-L-phenylalanine". Network pharmacology identified 144 potential target genes associated with 131 differential metabolites. Core targets included PLA2G4A, PPARG, PPARA, CYP3A4, and PTGS2. Molecular docking demonstrated that key differential metabolites, including (10E,12Z)-9-HODE, 13-OxoODE, and 2-Hydroxycinnamic acid, exhibited strong binding affinities with these core targets.</p> Conclusion <p>This study provides the first comprehensive evidence that Gurigumu-13 possesses significant hepatoprotective and antifibrotic properties. Its antifibrotic effects are mediated through the modulation of metabolic pathways and interactions with multiple molecular targets involved in inflammation, lipid metabolism, and oxidative stress. By integrating metabolomics with network pharmacology, this work offers novel insights into the mechanisms of Gurigumu-13 and supports its potential clinical application for treating liver fibrosis.</p>

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Integrative metabolomics and network pharmacology reveal the antifibrotic mechanisms of Gurigumu-13 in a rat model of hepatic fibrosis

  • 期刊论文

  • 发表日期：

    2026年3月7日

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  • Shuping Tong,
  • Anni,
  • Sudulugeqi,
  • Yukun Wang,
  • Xiang Li,
  • Wenbo Du

摘要

Background

Liver fibrosis, a common pathological progression in chronic liver diseases, can lead to irreversible cirrhosis and hepatocellular carcinoma if untreated. Gurigumu-13, a traditional herbal formulation, has demonstrated promising protective and therapeutic effects against liver fibrosis in clinical settings. However, its underlying antifibrotic mechanisms remain unclear.

Methods

A rat model of hepatic fibrosis was induced via intraperitoneal injection of dimethylnitrosamine (DMN). Rats were treated with high, medium, or low doses of Gurigumu-13. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) were measured to evaluate liver function. Hepatic hydroxyproline (Hyp), laminin (LN), alpha-smooth muscle actin (α-SMA), and type IV collagen (Col-IV) were measured to assess liver function. Liver tissues were subjected to hematoxylin–eosin (HE), Masson, and Sirius Red staining to evaluate histopathological changes and collagen deposition. The expression of alpha-smooth muscle actin (α-SMA) and type I collagen (Col-I) in liver tissue was analyzed by immunohistochemistry (IHC) and western blot (WB). Metabolomics analysis was performed on liver samples, followed by multivariate statistical analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, network pharmacology prediction, and molecular docking to explore differential metabolites, enriched metabolic pathways, potential target genes, and key ligand-receptor interactions.

Results

Gurigumu-13 significantly improved liver function by reducing serum ALT, AST, and ALP levels, TBIL, Hyp, LN, α-SMA, and Col-IV and alleviating hepatic histological damage in a dose-dependent manner (H-G13 vs. DMN, p < 0.001). It also downregulated the expression of fibrosis-related markers α-SMA and Col-I (H-G13 vs. DMN, p < 0001). A total of 227 differential metabolites were identified between the DMN and H-G13 groups, showing significant alterations in lipid, amino acid, and organic acid metabolism. KEGG pathway analysis revealed enrichment in pathways such as 5 significantly enriched metabolic pathways include "L-Tyrosine", "2-Hydroxycinnamic acid", "ortho-Hydroxyphenylacetic acid", "L-3-Phenyllactic acid", "N-Acetyl-L-phenylalanine". Network pharmacology identified 144 potential target genes associated with 131 differential metabolites. Core targets included PLA2G4A, PPARG, PPARA, CYP3A4, and PTGS2. Molecular docking demonstrated that key differential metabolites, including (10E,12Z)-9-HODE, 13-OxoODE, and 2-Hydroxycinnamic acid, exhibited strong binding affinities with these core targets.

Conclusion

This study provides the first comprehensive evidence that Gurigumu-13 possesses significant hepatoprotective and antifibrotic properties. Its antifibrotic effects are mediated through the modulation of metabolic pathways and interactions with multiple molecular targets involved in inflammation, lipid metabolism, and oxidative stress. By integrating metabolomics with network pharmacology, this work offers novel insights into the mechanisms of Gurigumu-13 and supports its potential clinical application for treating liver fibrosis.