Decoding the Anticancer Mechanism of Action of Kaempferol in Liver Cancer Cells via Transcriptomics, Network Pharmacology, Molecular Docking, Dynamics Simulations, and in vitro Validation

Indian Journal of Pharmaceutical Education and Research

  • Zhen He1Department of Oncology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan Hubei, CHINA.
  • Wei Liu2Department of Liver Disease, Yantai Qishan Hospital, Yantai Shandong, CHINA.
  • Na Su3Department of Critical Care Medicine, Shaanxi Rehabilitation Hospital, Xi’an Shaanxi, CHINA
  • Guoqiang Xing4Department of Oncology, The First Hospital of Weinan, Weinan Shaanxi, CHINA.

Volume 60 Issue 3 Pages 1206-1217

DOI: 10.5530/ijper.20262120

Abstract

Background: Kaempferol, a dietary flavonoid with proven antioxidant and antiinflammatory properties, has garnered significant interest in cancer research for its ability to modulate multiple oncogenic pathways, making it a compelling candidate for multitargeted therapy in addressing the considerable health burden of liver cancer. Objectives: To elucidate the therapeutic potential of kaempferol through network pharmacology, and in vitro experimental methodology. Materials and Methods: The pharmacological and physico-chemical properties of kaempferol were assessed using SwissADME and Protox-3.0. Target prediction utilized SuperPred and SwissTargetPrediction, filtered for liver cancer-specific genes through GeneCards. Protein-Protein Interaction (PPI) networks were constructed in Cytoscape, with hub genes identified via cytoHubba. Functional enrichment analyses, molecular docking, and dynamics were conducted, supported by GEPIA2 and TIMER analyses. HEP-G2 cell assays evaluated cell cytotoxicity, cell migration, apoptosis, and cell cycle phase distribution effects. Results: Kaempferol exhibited favorable drug-likeness, low toxicity, and potent interactions with liver cancer targets. Hub genes (GSK3B, MMP9, STAT1) were identified, linked to key cancer pathways (Wnt, PI3K-Akt, ECM-receptor). Molecular docking demonstrated high affinity for GSK3B (-8.9 kcal/mol), MMP9 (-9.2 kcal/mol), and STAT1 (-7 kcal/mol), with stable interactions validated by dynamics. Expression analyses revealed upregulation of these genes in liver cancer, correlated with immune infiltration patterns. Experimentally, kaempferol reduced HEP-G2 cell viability in a dose-dependent manner, significantly inhibited cell migration, induced cell apoptosis (early and late), and arrested cells at the G2/M phase. Conclusion: Kaempferol regulates critical pathways in liver cancer, exhibiting potent anticancer effects through induction of apoptosis, inhibition of cell migration, and cell cycle arrest, thereby positioning it as a compelling prospect for therapeutic development.

Keywords

  • Natural Products
  • Bioinformatics
  • Network Pharmacology
  • Liver cancer
  • Molecular
  • Docking
  • Apoptosis
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