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Purpose <p>This study systematically elucidates that Echinacoside exerts its anti-liver cancer effect through a “multi-target-core pathway” pattern, which may involve modulation of the PI3K-Akt signaling pathway.</p> Methods <p>A multi-dimensional research strategy was employed by integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experimental validation. Potential targets of Echinacoside and liver cancer-related genes were predicted from multiple databases. Core targets were screened via PPI network analysis, followed by GO and KEGG enrichment analyses. Molecular docking and 100 ns molecular dynamics simulations were performed to validate binding affinities and conformational stability of Echinacoside with core target proteins. Bioinformatics analyses using public databases were conducted to evaluate the clinical relevance of core targets. Finally, in vitro experiments, including CCK-8 assay, ROS detection, and Western blot, were carried out in HepG2 and Huh7 cells to validate the anti-proliferative effect and regulatory mechanism on the PI3K-Akt pathway.</p> Results <p>A total of 205 Echinacoside targets and 6270 liver cancer-related genes were obtained, yielding 103 common targets. PPI network screening identified 10 core targets. Enrichment analyses indicated significant enrichment in the PI3K-Akt signaling pathway. Molecular docking showed strong binding affinities between Echinacoside and core targets, with particularly stable binding to MMP9, MAPK1, ANXA5, and EGFR. Molecular dynamics simulations confirmed the conformational stability of Echinacoside complexes with MMP9, MAPK1, and ANXA5. Bioinformatics analysis revealed that core targets were significantly overexpressed in liver cancer tissues, correlated with poor prognosis, and associated with tumor immune infiltration. In vitro experiments demonstrated that Echinacoside inhibited HepG2 and Huh7 cell proliferation in a concentration-dependent manner, induced ROS accumulation, and significantly downregulated the phosphorylation levels of PI3K and Akt without affecting their total protein expression.</p> Conclusion <p>This study suggests that Echinacoside may exert its anti-liver cancer effects through a “multi-target-core pathway” pattern involving modulation of the PI3K-Akt signaling pathway. The data indicate that its effects are associated with reduced phosphorylation of PI3K and Akt. These findings provide a systematic theoretical and experimental basis for developing Echinacoside as a potential candidate anti-liver cancer drug and offer a methodological paradigm for researching anti-cancer mechanisms of natural products.</p>

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Investigating the Mechanism of Echinacoside against Liver Cancer involving Modulation of the PI3K-Akt Pathway through Multiple Targets based on Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation

  • 期刊论文

  • 发表日期：

    2026年6月26日

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  • Yao Gao,
  • Jianjin Guo,
  • Zhoujing Zhu,
  • Fangfang Ding

摘要

Purpose

This study systematically elucidates that Echinacoside exerts its anti-liver cancer effect through a “multi-target-core pathway” pattern, which may involve modulation of the PI3K-Akt signaling pathway.

Methods

A multi-dimensional research strategy was employed by integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experimental validation. Potential targets of Echinacoside and liver cancer-related genes were predicted from multiple databases. Core targets were screened via PPI network analysis, followed by GO and KEGG enrichment analyses. Molecular docking and 100 ns molecular dynamics simulations were performed to validate binding affinities and conformational stability of Echinacoside with core target proteins. Bioinformatics analyses using public databases were conducted to evaluate the clinical relevance of core targets. Finally, in vitro experiments, including CCK-8 assay, ROS detection, and Western blot, were carried out in HepG2 and Huh7 cells to validate the anti-proliferative effect and regulatory mechanism on the PI3K-Akt pathway.

Results

A total of 205 Echinacoside targets and 6270 liver cancer-related genes were obtained, yielding 103 common targets. PPI network screening identified 10 core targets. Enrichment analyses indicated significant enrichment in the PI3K-Akt signaling pathway. Molecular docking showed strong binding affinities between Echinacoside and core targets, with particularly stable binding to MMP9, MAPK1, ANXA5, and EGFR. Molecular dynamics simulations confirmed the conformational stability of Echinacoside complexes with MMP9, MAPK1, and ANXA5. Bioinformatics analysis revealed that core targets were significantly overexpressed in liver cancer tissues, correlated with poor prognosis, and associated with tumor immune infiltration. In vitro experiments demonstrated that Echinacoside inhibited HepG2 and Huh7 cell proliferation in a concentration-dependent manner, induced ROS accumulation, and significantly downregulated the phosphorylation levels of PI3K and Akt without affecting their total protein expression.

Conclusion

This study suggests that Echinacoside may exert its anti-liver cancer effects through a “multi-target-core pathway” pattern involving modulation of the PI3K-Akt signaling pathway. The data indicate that its effects are associated with reduced phosphorylation of PI3K and Akt. These findings provide a systematic theoretical and experimental basis for developing Echinacoside as a potential candidate anti-liver cancer drug and offer a methodological paradigm for researching anti-cancer mechanisms of natural products.