〔Abstract〕 Objective To explore the effect of silencing APE-1 on transcriptome expression and TNF signaling pathway in hepatoma cell Hep 3 B. Methods A hepatocellular carcinoma Hep 3 B stable cell line silencing APE-1 expression was subjected to transcriptome sequencing. The experimental group was cells with silencing APE-1 expression, and the control group was cells transfected with blank plasmid(n=3). Bioinformatics analysis of differentially expressed genes, and functional enrichment of GO, KEGG, and DO, and protein interaction networks of differential genes were conducted. The key genes of TNF signaling pathway, TNFAIP3 and MAP2 K6 were detected by real-time PCR in the experimental/control group cells. Ten pairs of liver cancer/cancer adjacent clinical samples were collected and their protein expression was detected by immunohistochemistry. Based on data from 374 patients with liver cancer in the TCGA database, the correlation between APE-1 and TNFAIP3, APE-1 and MAP2 K6 expression was analyzed. Results Silencing APE-1 resulted in a up-regulation of 84 genes and down-regulation of 39 genes in hepatoma cell Hep 3 B. The top 10 differential genes were APE-1, CEMIP, MAP2 K6, TAF11 L11, CNGB1, COL5 A3, OTULINL, DNAJC12, FOLR1, and ACKR3. RT-PCR verified that TNFAIP3 and MAP2 K6 were down-regulated in hepatoma cell Hep 3 B silencing APE-1. TNFAIP3 and MAP2 K6 were highly expressed in clinical liver cancer tissue samples, and there was a significant positive correlation between APE-1 and TNFAIP3, APE-1 and MAP2 K6 expression(P<0.001). Conclusion APE-1 is a key anti-tumor gene in the development of liver cancer, which may play a role in affecting the TNF signaling pathway.