<p>This study was performed to identify crucial oncogenes modulated by DNA methylation in hepatocellular carcinoma (HCC) and look for new drugs for HCC treatment. The data of TCGA-LIHC cohort were obtained from UCSC database. Weighted gene co-expression network analysis and multiple machine learning algorithms were applied to screen the crucial prognosis-related genes in HCC. Then these genes were further screened by DNA methylation status. Ten-eleven translocation 1 (TET1) was overexpressed in HCC cell lines, and its biological functions and regulatory effects on the oncogenes were explored by qPCR, methylation-specific polymerase chain reaction, cell viability assay, Western blot, etc. Molecular docking was applied to evaluate the binding affinity between atractylenolide I (AT-I) and TET1, and the tumor-suppressive functions of AT-I were examined with both in vitro and in vivo models. In this work, 12 crucial genes related to HCC prognosis were obtained, among which six genes were with differential methylation status in HCC tissues, including AKR1B10, ALPK3, NQO1, NT5DC2, SFN, and SPP1. The expression levels of ALPK3 and NT5DC2 were positively regulated by TET1, the crucial mediator of demethylation. TET1 overexpression increased the viability and stemness of HCC cells. AT-I had good binding affinity with TET1, and repressed its activity. AT-I promoted the methylation of ALPK3 and NT5DC2 promoter regions, and reduced their expression, and repressed the growth of HCC cells. In summary, DNA methylation contributes to HCC progression, and AT-I represses the malignancy of HCC cells by inhibiting TET1-mediated abnormal DNA demethylation.</p>