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<p>Breast cancer is a highly prevalent cancer among women worldwide. The triple-negative breast cancer (TNBC) subtype has a particularly poor prognosis, is characterized by high invasiveness and low survival rates, and is currently a major challenge in the clinical treatment of breast cancer. This study aims to analyze the drug metabolism pathways of TNBC and provide a preclinical foundation for potential therapeutic strategies. Metabolomics integrated with network pharmacology was employed to elucidate the mechanism of action of icariin (ICA) in TNBC. The inhibitory effects of ICA on TNBC cell proliferation, migration, invasion, and apoptosis were detected via CCK-8, wound healing, Transwell and flow cytometry assays, among other methods. Differentially abundant metabolites were identified via LC‒MS-based untargeted metabolomics, complemented by network pharmacology prediction of hub targets. The binding conformation of ICA to target proteins was simulated via AutoDock, and a target–metabolite regulatory network was constructed. The mRNA expression of the hub targets and associated pathway proteins was subsequently validated via qRT‒PCR and Western blotting. ICA significantly inhibited the proliferation, migration, and invasion of TNBC cells while inducing apoptosis (<i>P</i> &lt; 0.01). Metabolomic analysis revealed 311 differentially abundant metabolites, with pathways regulated by these metabolites significantly enriched in three core processes: energy metabolism, biosynthesis of macromolecules, and transmembrane transport. By integrating metabolomic and network pharmacology analyses, four targets (AKT1, SRC, NFKB1, and IL6) were identified, with the PI3K-AKT pathway pinpointed as the core mechanism mediating the metabolic perturbations observed in this study. Molecular docking revealed strong binding affinity between ICA and these targets. qRT‒PCR confirmed significant downregulation of the core target mRNAs, and Western blotting further validated the ICA-mediated suppression of key PI3K-AKT pathway proteins (e.g., p-PI3K/PI3K and p-AKT/AKT ratios). This study integrated metabolomic and network pharmacology analyses and revealed that ICA suppresses the malignant phenotypes of TNBC by targeting AKT1/SRC/NFKB1 to inhibit the PI3K-AKT pathway, thereby establishing a mechanistic foundation for its clinical application.</p>

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Integrated metabolomics and network pharmacology reveals that icariin antagonizes malignant phenotypes in triple-negative breast cancer via AKT1/SRC/NFKB1-mediated PI3K‒AKT pathway inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月25日

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  • Haiyang Hu,
  • Shenghan Gao,
  • Jie Liu,
  • Wen Wang,
  • Kexin Chang,
  • Yulong Yin,
  • Xianghua Liu,
  • Qingjie Meng,
  • Wenzhen Shi,
  • Yonggang Lv

摘要

Breast cancer is a highly prevalent cancer among women worldwide. The triple-negative breast cancer (TNBC) subtype has a particularly poor prognosis, is characterized by high invasiveness and low survival rates, and is currently a major challenge in the clinical treatment of breast cancer. This study aims to analyze the drug metabolism pathways of TNBC and provide a preclinical foundation for potential therapeutic strategies. Metabolomics integrated with network pharmacology was employed to elucidate the mechanism of action of icariin (ICA) in TNBC. The inhibitory effects of ICA on TNBC cell proliferation, migration, invasion, and apoptosis were detected via CCK-8, wound healing, Transwell and flow cytometry assays, among other methods. Differentially abundant metabolites were identified via LC‒MS-based untargeted metabolomics, complemented by network pharmacology prediction of hub targets. The binding conformation of ICA to target proteins was simulated via AutoDock, and a target–metabolite regulatory network was constructed. The mRNA expression of the hub targets and associated pathway proteins was subsequently validated via qRT‒PCR and Western blotting. ICA significantly inhibited the proliferation, migration, and invasion of TNBC cells while inducing apoptosis (P < 0.01). Metabolomic analysis revealed 311 differentially abundant metabolites, with pathways regulated by these metabolites significantly enriched in three core processes: energy metabolism, biosynthesis of macromolecules, and transmembrane transport. By integrating metabolomic and network pharmacology analyses, four targets (AKT1, SRC, NFKB1, and IL6) were identified, with the PI3K-AKT pathway pinpointed as the core mechanism mediating the metabolic perturbations observed in this study. Molecular docking revealed strong binding affinity between ICA and these targets. qRT‒PCR confirmed significant downregulation of the core target mRNAs, and Western blotting further validated the ICA-mediated suppression of key PI3K-AKT pathway proteins (e.g., p-PI3K/PI3K and p-AKT/AKT ratios). This study integrated metabolomic and network pharmacology analyses and revealed that ICA suppresses the malignant phenotypes of TNBC by targeting AKT1/SRC/NFKB1 to inhibit the PI3K-AKT pathway, thereby establishing a mechanistic foundation for its clinical application.