In this study, the role of DUXAP8 in promoting malignant phenotype and chemotherapy resistance in HCC was revealed, and it was confirmed for the first time that Mettl3-mediated m6A modifications were involved in the upregulation of DUXAP8. In summary, it was found that DUXAP8 exhibited high expression in sorafenib-treated PDX models and was positively correlated with the TNM cancer stage, tumor size, microvascular invasion, and distant metastasis. Here, DUXAP8 is linked to hepatocellular carcinoma.