Abstract
Objective: Dihydroartemisinin (DHA) is an active metabolite of artemisinin and its derivatives, which is a potent drug extensively applied in clinical treatment of malaria. The antitumor properties of DHA have received increasing attention. However, there is no systematic summary on the pharmacological mechanisms of DHA against esophageal carcinoma (ESCA). The present study implemented network pharmacology- and molecular docking-based approaches to unveil the pharmacological mechanisms of DHA against ESCA. Methods: DHA targets were accessed through integrating the SwissTargetPrediction, HERB, as well as BATMAN-TCM platforms. In TCGA-ESCA dataset, genes with differential expression were screened between 161 ESCA and 11 normal tissue specimens. DHA targets against ESCA were obtained through intersection. Their biological significance was evaluated with functional enrichment analysis. A prognostic signature was established via uni- and multivariate cox regression analyses. DHA-target interactions were predicted via molecular docking. Molecular dynamics simulation was implemented to examine the stability of DHA binding to potential targets. Results: The study predicted 160 DHA targets as well as 821 genes with differential expression in ESCA. Afterwards, 16 DHA targets against ESCA were obtained, which remarkably correlated to cell cycle progression. The ADORA2B- and AURKA-based prognostic signature exhibited the reliability and independency in survival prediction. The stable docking of DHA-ADORA2B and DHA-AURKA was confirmed. Conclusion: Collectively, this study systematically revealed the basis and mechanism of DHA against ESCA through targeting multi-target and multi-pathway mechanisms, and thus offered theoretical and scientific basis for the clinical application of DHA.