Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty concerns the nature of the mechanisms of Nrf2 activation in hepatocarcinogenesis. Indeed, it remains unclear what is the main mechanism behind the sustained activation of the Keap1/Nrf2 pathway in hepatocarcinogenesis. This raises doubts about the best strategies to therapeutically target this pathway. In this review, we will analyze and discuss our present knowledge concerning the role of Nrf2 in hepatic physiology and pathology, including hepatocellular carcinoma. In particular, we will critically examine and discuss some findings originating from animal models that raise questions that still need to be adequately answered.
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