AbstractPurposeHepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The occurrence and development of HCC are closely related to epigenetic modifications. Epigenetic modifications can regulate gene expression and related functions through DNA methylation. This paper presents an association analysis method of HCC‐related hub proteins and hub genes.Experimental designBioinformatics analysis of HCC‐related DNA methylation data is carried out to clarify the molecular mechanism of HCC‐related genes and to find hub genes (genes with more connections in the network) by constructing in the gene interaction network. This paper proposes an accurate prediction method of protein–protein interaction (PPI) based on deep learning model DeepSG2PPI. The trained DeepSG2PPI model predicts the interaction relationship between the synthetic proteins regulated by HCC‐related genes.ResultsThis paper finds that four genes are the intersection of hub genes and hub proteins. The four genes are: FBL, CCNB2, ALDH18A1, and RPLP0. The association of RPLP0 gene with HCC is a new finding of this study. RPLP0 is expected to become a new biomarker for the treatment, diagnosis, and prognosis of HCC. The four proteins corresponding to the four genes are: ENSP00000221801, ENSP00000288207, ENSP00000360268, and ENSP00000449328.Conclusions and clinical relevanceThe association between the hub genes with the hub proteins is analyzed. The mutual verification of the hub genes and the hub proteins can obtain more credible HCC‐related genes and proteins, which is helpful for the diagnosis, treatment, and drug development of HCC.