Taken together, these data suggested that loss of NF1 could activate the PI3K/AKT and MAPK/ERK signaling pathways to promote lenvatinib resistance in HCC, while loss of NF1 DUSP9 could activate the MAPK/ERK but not the PI3K/AKT pathway to promote lenvatinib resistance, and the potential downstream regulatory target gene is FOXO3. Here, FOXO3 is linked to hepatocellular carcinoma.