Abstract
Simple SummaryAlthough the Keap1-Nrf2 pathway represents a powerful cell defense mechanism against a variety of toxic insults, its role in acute or chronic liver damage and tumor development is not completely understood. This review addresses how Nrf2 is involved in liver pathophysiology and critically discusses the contrasting results emerging from the literature. The aim of the present report is to stimulate further investigation on the role of Nrf2 that could lead to define the best strategies to therapeutically target this pathway.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.
Highlights
The Kelch-like ECH-associated protein 1 and nuclear factor-like 2(Keap1/Nrf2) pathway is one of the most important cellular defense systems against environmental stress
Nrf2 is a basic leucine zipper transcription factor belonging to the Cap N0 Collar (CNC) family that binds to DNA unique sequences, named antioxidant responsive elements (AREs) [1,2,3]
Nrf2-KO mice were more susceptible to acetaminophen-induced acute liver injury than wild type (WT) animals [29], and it has been proposed that this protective role is played by the p62/Nrf2/Keap1 axis [30]
Summary
The Kelch-like ECH-associated protein 1 and nuclear factor (erythroid-derived-2)-like 2. (Keap1/Nrf2) pathway is one of the most important cellular defense systems against environmental stress. Keap mediates Nrf polyubiquitination and, its proteasomal degradation. Under oxidative stress, such as exposure to reactive oxygen. Nrf signaling attenuates the pathological features of chronic liver injuries by suppressing oxidative stress (due to the unbalance between increased ROS production and decreased antioxidant defenses), which is known to be the key player in the development and progression of chronic liver damage [11]. Several studies provided evidence that hyperactivation of the Nrf pathway creates an environment that favors the survival of DNA-damaged cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy, favoring cancer progression (Reviewed in [12,13]). The identification of a dark side of Nrf has generated new interest and some concern, because it is still unclear whether interference with Nrf results in a beneficial, or in a harmful, condition
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