In this study, we demonstrated that circUCK2(2,3) overexpression enhances the synergistic killing effects of lenvatinib when combined with multiple EGFR inhibitors in HCC cells and in PDX clinical models, suggesting that tumor circUCK2(2,3) levels may present a promising biomarker predicting the response to combined treatment of lenvatinib and EGFR inhibitors. This evidence concerns the gene EGFR and hepatocellular carcinoma.