The main findings of this study can be summarized as follows: 1) using a multistage model of nutritional hepatocarcinogenesis, we have provided evidence that a progressive decrease in the frequency of Nrf2 mutations occurs along with HCC progression; 2) in spite of this decrease, sustained Nrf2-Keap1 pathway activation characterizes all stages of the tumorigenic process; 3) activation of the Nrf2-Keap1 pathway at late stages is the consequence of accumulation of p62, which competes with Nrf2 for Keap1 binding, thus leading to an Nrf2-induced antioxidative response of cancer cells. Here, NFE2L2 is linked to hepatocellular carcinoma.