OBJECTIVE To explore the mechanism of action of Guilu Erxian Jiao combined with cisplatin in the treatment of non-small cell lung cancer through network pharmacology prediction and animal experiment verification.

METHODS The active ingredients, target proteins, and disease targets of Guilu Erxian Jiao were retrieved and summarized from various databases including TCMSP, HERB, PubChem, Swiss, Genecard, OMIM, PharmGkb, and TTD. The protein interaction network was constructed using the STRING database, and the topological analysis and screening of core targets were performed using Cytoscape3.9.0. A drug-ingredient-target-disease network diagram was constructed using Cytoscape3.9.0, gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed using R language. A mouse model of lung adenocarcinoma was constructed, and HE staining was used to determine the pathological changes in lung tissue of the model and treatment groups. Open field experiments were performed to evaluate the activity and anxiety of the mice in each group, and RT-qPCR and Western blotting were used to detect the mRNA and protein expression in the lung tissue of the mice in each group.

RESULTS A total of 81 active ingredients and 190 target proteins of Guilu Erxian Jiao were obtained, as well as 6002 non-small cell lung cancer target proteins, and a total of 149 intersecting targets were identified. GO enrichment analysis yielded 2550 results, including 2300 in the biological process, 73 in the cellular component, and 177 in the molecular function. KEGG enrichment analysis yielded 176 related pathways, among which the hypoxia inducible factor-1(HIF-1) signaling pathway was found to be significantly associated. In the animal experiments, it was found that lung cancer mice showed solid pathological changes and partial pathological nuclear division in lung tissue seven days after modeling, and the weight was significantly reduced compared to the control group, indicating the successful establishment of the model. Monitoring of the weight and diet of the mice in each group showed that Guilu Erxian Jiao could increase the weight and diet of the lung cancer mice. The open field test results showed that Guilu Erxian Jiao could effectively improve cancer-related fatigue in mice and also improve adverse reactions after cisplatin injection. HE staining showed that Guilu Erxian Jiao could reduce the pathological changes in lung tissue of the mice. RT-qPCR and Western blotting showed that Guilu Erxian Jiao could down-regulate the mRNA and protein expression of HIF-1α, VEGF, and iNOS in the lung tissue of the mice.

CONCLUSION Guilu Erxian Jiao combined with cisplatin can effectively treat non-small cell lung cancer, and its treatment has the characteristics of multiple components, targets, and pathways, and the HIF-1 signaling pathway may be one of the pathways by which it works.