These findings are important in several senses: first, it is a discovery that NF1 and DUSP9 are two key resistance genes for lenvatinib treatment, and that these two genes are potential therapeutic targets and valuable predictors of lenvatinib resistance in HCC; second, it is a demonstration that PI3K/AKT and MAPK/ERK are the resistance signaling pathways of NF1 and DUSP9; third, it provides evidence that trametinib might synergize with lenvatinib to treat HCC more effectively. Here, DUSP9 is linked to hepatocellular carcinoma.