Network Pharmacological Study of the Active Ingredient of Panax Notoginseng Saponins for the Treatment of Lung Cancer by Inhibiting AKR1C3

Background: Lung cancer is the malignancy with the second highest diagnostic rate and the leading cause of cancer-related death. Objective: This study aims to investigate the potential mechanism and molecular targets of Panax notoginseng saponins (PNS) in inhibiting lung cancer through network pharmacology. Methods: Pharmacodynamic targets of each compound of PNS were searched from TargetNet, SwissTargetPrediction, and BatMan-TCM databases. Next, the differential expression genes (DEGs) in lung cancer were obtained from the Gene Expression Omnibus (GEO) database and screened by R package. Later, the STRING 11.0 database was utilized to analyze the protein-protein interaction (PPI) network of common targets of PNS-lung cancer, clusterProfiler to perform gene ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the common targets, and Cytoscape 3.8.0 to construct and analyze the "ingredient-target" network for the common targets of PNS-lung cancer. Results: A total of 154 potential pharmacodynamic targets of PNS, 2399 DEGs of lung cancer-related diseases, and 21 common targets of PNS-lung cancer were obtained by database search and screening. The 21 common targets were mainly involved in biological processes (such as small molecule metabolism and cytokine production) and were major components of cellular structures (such as neuronal cell bodies and membrane rafts). Besides, these targets could function as carboxylic ester hydrolases, G protein-coupled amine receptors, and oxidoreductase. They were mainly enriched in 14 signaling pathways, like neuroactive ligand-receptor interaction, regulation of lipolysis in adipocytes, and calcium signaling pathway. Furthermore, the molecular docking results revealed that aldo-keto reductase family 1 member C3 (AKR1C3) and melanin metabolic enzyme (MME) may be direct targets of ginsenoside Rg1 and notoginsenoside R2. Conclusion: Our study showed that ginsenosides inhibit the progression of lung cancer through multiple targets and pathways. More importantly, PNS may treat lung cancer by directly inhibiting AKR1C3.