BackgroundHepatocellular carcinoma (HCC) is a primary malignant tumor of the liver, and pyroptosis has been identified as a novel cellular program that plays a role in numerous diseases including cancer. However, the functional role of pyroptosis in HCC remains unclear. The purpose of this study is to explore the relationship between the two found hub genes and provide targets for clinical treatment.MethodsThe Cancer Genome Atlas (TCGA) database was used to collect the gene data and clinically-related information of patients with HCC. After the differentially expressed genes (DEGs) were identified, they were intersected with the genes related to pyroptosis, and a risk prediction model was established to predict the overall survival (OS). Subsequently, drug sensitivity analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) was used to analyze the biological characteristics of the DEGs. Different immune cell infiltration and related pathways were analyzed, and hub genes were identified by protein-protein interaction (PPI). Finally, the expression of hub genes was verified by real-time quantitative PCR (qRT-PCR) and immunohistochemistry.ResultsWe conducted a comprehensive bioinformatics analysis to investigate the molecular mechanisms of pyroptosis in hepatocellular carcinoma (HCC). A total of 8,958 differentially expressed genes were identified, and 37 differentially expressed genes were associated with pyroptosis through intersection. Moreover, we developed an OS model with excellent predictive ability and discovered the differences in biological function, drug sensitivity, and immune microenvironment between high-risk and low-risk groups. Through enrichment analysis, we found that the differentially expressed genes are related to various biological processes. Then, 10 hub genes were identified from protein-protein interaction networks. Finally, midkine (MDK) was screened from the 10 hub genes and further verified by PCR and immunohistochemistry, which revealed its high expression in HCC.ConclusionWe have developed a reliable and consistent predictive model based on the identification of potential hub genes, which can be used to accurately forecast the prognosis of patients, thus providing direction for further clinical research and treatment.