Study on the Mechanism of Formononetin Against Hepatocellular Carcinoma: Regulating Metabolic Pathways of Ferroptosis and Cell Cycle

作者：Ning Bao, Zichao Chen, B. Li, Haolin Yang, Xiao Li, Zhen Zhang · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26062578 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Cancer, Lipids, and Metabolism

Formononetin (FM), an isoflavone with a range of anti-cancer activities, has not been fully elucidated regarding its anti-hepatocellular carcinoma (HCC) mechanisms. Therefore, this study aims to explore the underlying mechanisms of FM using a comprehensive pharmacology model based on computational technologies and omics technology. A network pharmacology approach was applied to detect the components and targets. A mathematical formula was used to evaluate the network contribution index (CI). Bioinformatics analysis was used to analyze clinical data related to HCC targets corresponding to the core component, and molecular docking simulations were conducted to assess binding activity. The results showed that FM induces oxidative DNA damage through ROS generation and triggers G2/M phase cell cycle arrest via the Chk1/Cdc25C/CDK1/CCNB1 signaling pathway. Subsequently, UPLC-MS/MS was applied for the analysis of differential metabolites and the exploration of distinct metabolic pathways. FM limited the synthesis of glutathione, promoted lipid peroxidation, and facilitated the generation of divalent iron. Finally, a colony formation assay, Western blot, and molecular dynamics simulation methods were executed to further validate the metabolomic results. FM exhibited a strong binding affinity for glutathione peroxidase 4 (GPX4). In addition, FM induces ferroptosis by inhibiting the p53/xCT/GPX4 signaling pathway. In vivo, FM could inhibit tumor growth. Conclusions: FM could induce DNA...