摘要Background:Hepatocellular carcinoma (HCC) has a poor long-term prognosis. The competition of circu-lar RNAs (circRNAs) with endogenous RNA is a novel tool for predicting HCC prognosis. Based on the alterations of circRNA regulatory networks,the analysis of gene modules related to HCC is feasible.Methods:Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in HCC. Gene function,pathway,and protein interaction analyses were performed for the differentially expressed genes (DEGs) in this regulatory network. In the protein-protein interaction network,hub genes were identified and subjected to regression analysis,producing an optimized four-gene signature for prognostic risk stratification in HCC patients. Anti-HCC drugs were excavated by assessing the DEGs between the low-and high-risk groups. A circRNA-microRNA-hub gene subnetwork was constructed,in which three hallmark genes,KIF4A,CCNA2,and PBK,were subjected to functional enrichment analysis.Results:A four-gene signature ( KIF4A,CCNA2,PBK,and ZWINT ) that effectively estimated the overall sur-vival and aided in prognostic risk assessment in the The Cancer Genome Atlas (TCGA) cohort and Inter-national Cancer Genome Consortium (ICGC) cohort was developed. CDK inhibitors,PI3K inhibitors,HDAC inhibitors,and EGFR inhibitors were predicted as four potential mechanisms of drug action (MOA) in high-risk HCC patients. Subsequent analysis has revealed that PBK,CCNA2,and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion,regulating microsatellite instability (MSI),and exerting an impact on HCC progression.Conclusions:The present study highlights the role of the circRNA-related regulatory network,identifies a four-gene prognostic signature and biomarkers,and further identifies novel therapy for HCC.