Exploring the key pathogenic mechanisms and potential intervention targets for Sophorae Flavescentis radix in managing bone metastasis of lung cancer based on network pharmacology and molecular docking techniques.

Abstract

Background: Lung cancer often metastasizes to the bone, which significantly complicates treatment and worsens patient prognosis. Thus, new therapeutic strategies need to be established. Using network pharmacology and bioinformatics analysis, this study sought to determine the molecular targets and associated mechanisms of the traditional Chinese medicine (TCM) Sophorae Flavescentis radix in the treatment of lung cancer bone metastasis.

Methods: The active components of Sophorae Flavescentis radix were screened using the TCM Systems Pharmacology (TCMSP) platform based on drug-likeness and oral bioavailability. The target genes of these active compounds were obtained from the DrugBank database. Differentially expressed genes (DEGs) between primary and bone metastatic lung cancer samples were screened in the GSE175601 dataset from the Gene Expression Omnibus (GEO) database using GEO2R. The intersecting DEGs from both groups were used to construct a Venn diagram to identify the candidate target genes. The expression and prognostic relevance of these genes were validated in The Cancer Genome Atlas (TCGA) database. The GeneMania and Search Tool for Recurring Instances of Neighbouring Genes (STRING) databases were used to generate the protein-protein interaction networks. Molecular docking was performed using the PubChem, Protein Data Bank (PDB), and CB-DOCK2 databases. A Gene Set Enrichment Analysis (GSEA) was conducted to explore the possible mechanisms of action.

Results: In the TCMSP database, 28 active compounds and 227 target genes of the Sophorae Flavescentis radix were identified. In total, 952 DEGs related to lung cancer bone metastasis were found in the GSE175601 dataset from the GEO database. Five common DEGs were identified via Venn diagram construction (i.e., F10, JUN, AKR1B1, MMP1, and CCND1). MMP1 was selected as the candidate gene. MMP1 was upregulated in lung cancer tissues, and patients with low MMP1 expression had better survival rates than those with high MMP1 expression (P<0.05). MMP1 has an affinity of -8.9 with luteolin. The GSEA results suggested that MMP1 might influence biological processes in lung cancer by participating in pathways such as chemokine signaling, apoptosis, Wingless/Integrated (Wnt) signaling, tumor protein p53-regulated cell cycle arrest, Hedgehog signaling, and mitogen-activated protein kinase signaling.

Conclusions: Patients with lower MMP1 levels had prolonged overall survival and may serve as a novel predictive biomarker for lung cancer. Sophorae Flavescentis radix appears to exert therapeutic effects on lung cancer bone metastasis by inhibiting MMP1 expression and modulating the abnormal activation of the Wnt pathway. Our findings further extend the understanding of the pathogenic mechanisms and potential therapeutic interventions of Sophorae Flavescentis radix in lung cancer bone metastasis, providing a theoretical basis for clinical diagnosis and treatment research.