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<p>Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide, characterized by high morbidity and poor prognosis. Although traditional Chinese herbal formulas have shown promising therapeutic potential, their multi-target mechanisms in CRC are still poorly understood. In this study, we systematically explored the anti-CRC mechanisms of Taohong-Siwu Decoction (THSWD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics simulation, and preliminary in vitro validation. Differential expression and weighted gene co-expression network analyses were conducted based on the GEO dataset GSE44076. The predicted targets of THSWD active compounds were intersected with differentially expressed and module-related genes, and seven machine learning algorithms were employed to identify core targets. Functional enrichment (GO and KEGG) and immune infiltration (CIBERSORT) analyses were performed, followed by molecular docking analysis, external validation using two independent GEO datasets, GSE9348 and GSE23878, molecular dynamics simulation, and experimental validation in HCT116 cells. A total of 1639 differentially expressed genes were identified, among which five key genes—CPT1A, CMA1, BCHE, CA7, and CA1—were screened and found to be significantly downregulated in CRC tissues. These genes were associated with enrichment in nitrogen metabolism, cell cycle regulation, and p53 signaling pathways. Immune infiltration analysis suggested differences in immune cell composition between CRC and normal tissues, and the expression of core genes was associated with specific immune cell subsets. Molecular docking further demonstrated that representative THSWD compounds, including baicalein, β-sitosterol, kaempferol, quercetagetin, and quercetin, exhibited stable binding affinities with these core proteins. Molecular dynamics simulation suggested that CA1–kaempferol complex exhibited the most favorable overall dynamic stability among the representative complexes. In vitro experiments further showed that kaempferol suppressed HCT116 cell viability, migration, and invasion, increased CA1 mRNA expression, and that CA1 knockdown partially attenuated kaempferol-induced apoptosis. Collectively, these findings suggest that THSWD may exert anti-CRC effects through multi-component synergy by targeting CPT1A, CMA1, BCHE, CA7, and CA1, modulating metabolic and signaling pathways, and remodeling the immune microenvironment. This study provides integrative computational and preliminary experimental evidence supporting the pharmacological basis of THSWD against CRC, warranting further in vivo and clinical validation.</p>

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Integrative analysis of network pharmacology and machine learning suggests potential anti-colorectal cancer mechanisms of Taohong-Siwu decoction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Dengchao Wang,
  • Chen Zhang,
  • Tao Jiang,
  • Jinshan Liu,
  • Yong Cheng

摘要

Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide, characterized by high morbidity and poor prognosis. Although traditional Chinese herbal formulas have shown promising therapeutic potential, their multi-target mechanisms in CRC are still poorly understood. In this study, we systematically explored the anti-CRC mechanisms of Taohong-Siwu Decoction (THSWD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics simulation, and preliminary in vitro validation. Differential expression and weighted gene co-expression network analyses were conducted based on the GEO dataset GSE44076. The predicted targets of THSWD active compounds were intersected with differentially expressed and module-related genes, and seven machine learning algorithms were employed to identify core targets. Functional enrichment (GO and KEGG) and immune infiltration (CIBERSORT) analyses were performed, followed by molecular docking analysis, external validation using two independent GEO datasets, GSE9348 and GSE23878, molecular dynamics simulation, and experimental validation in HCT116 cells. A total of 1639 differentially expressed genes were identified, among which five key genes—CPT1A, CMA1, BCHE, CA7, and CA1—were screened and found to be significantly downregulated in CRC tissues. These genes were associated with enrichment in nitrogen metabolism, cell cycle regulation, and p53 signaling pathways. Immune infiltration analysis suggested differences in immune cell composition between CRC and normal tissues, and the expression of core genes was associated with specific immune cell subsets. Molecular docking further demonstrated that representative THSWD compounds, including baicalein, β-sitosterol, kaempferol, quercetagetin, and quercetin, exhibited stable binding affinities with these core proteins. Molecular dynamics simulation suggested that CA1–kaempferol complex exhibited the most favorable overall dynamic stability among the representative complexes. In vitro experiments further showed that kaempferol suppressed HCT116 cell viability, migration, and invasion, increased CA1 mRNA expression, and that CA1 knockdown partially attenuated kaempferol-induced apoptosis. Collectively, these findings suggest that THSWD may exert anti-CRC effects through multi-component synergy by targeting CPT1A, CMA1, BCHE, CA7, and CA1, modulating metabolic and signaling pathways, and remodeling the immune microenvironment. This study provides integrative computational and preliminary experimental evidence supporting the pharmacological basis of THSWD against CRC, warranting further in vivo and clinical validation.