Unraveling the mechanisms of antitumor action of Sophora flavescens flavonoids via network pharmacology and molecular simulation.

Cancer, particularly lung, liver, and other malignancies, remains a major global health challenge due to their high incidence, complex etiology, and resistance to conventional therapies. Flavonoids derived from Sophora flavescens (Kushen) have gained attention for their potential in cancer prevention and treatment. This study uses network pharmacology, based on Traditional Chinese Medicine's holistic approach, and molecular simulation techniques to explore the anticancer mechanisms of Sophora flavescens flavonoids, aiming to provide a theoretical basis for developing plant-based anticancer agents. Active compounds and their targets were identified through literature screening and target identification methods. A cancer-related protein-protein interaction (PPI) network was constructed to identify key therapeutic targets, helping to understand how these flavonoids exert multitarget anticancer effects. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses elucidated mechanisms related to cancer cell proliferation inhibition, apoptosis induction, and signaling pathway regulation. Network pharmacology analysis identified TP53, ESR1, SRC, AKT1, and MAPK1 as key anticancer targets, involved in essential biological processes like phosphorylation and protein kinase activity. KEGG analysis showed that these flavonoids modulate critical pathways, particularly PI3K-Akt and RAS/RAF/MEK/ERK. Molecular docking revealed that rutin and luteolin-7-O-gentiobioside strongly bind to MAPK1, with interaction energies of 77.1466 kcal/mol and 79.2011 kcal/mol, respectively, indicating promising anticancer effects. Additionally, compounds with different substitution positions, such as those with glycosylation at the 7-OH position or isoprenyl groups at the C-8 positions, exhibited significantly higher interaction energies. Non-covalent interaction analysis further clarified how these flavonoids enhance anticancer effects through stable binding, with hydrogen bonds and hydrophobic contacts stabilizing interactions with MAPK1. Molecular dynamics simulations also confirmed the stability of these interactions, and binding free energy calculations revealed that luteolin-7-O-gentiobioside and rutin exhibited the lowest binding free energies (- 153.7841 kcal/mol and - 132.7434 kcal/mol, respectively), significantly outperforming the original ligand (- 57.7209 kcal/mol), further supporting the therapeutic potential of these compounds. To complement these findings, in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions were employed to evaluate the pharmacokinetic and safety profiles of rutin and luteolin-7-O-gentiobioside. The systematic analysis revealed critical issues in solubility, blood-brain barrier penetration, and hepatotoxicity, providing strategic guidance for structural optimization and formulation design. This study provides valuable insights into the multitarget anticancer mechanisms of Sophora flavescens flavonoids and supports their potential as plant-derived anticancer agents. However, further experimental and clinical studies, especially integrating TCM practice, are needed to validate these findings.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00338-0.