Nfe2l2, also known as NRF2 (nuclear factor, erythroid 2 like 2), is a master regulator of cellular antioxidant responses. It is a key component of the KEAP1-Nfe2l2 pathway, which is pivotal for maintaining cell homeostasis. Under normal conditions, Nfe2l2 is repressed by KEAP1; however, upon activation, it can initiate a series of antioxidant and cytoprotective responses, playing a crucial role in various biological processes and disease conditions [3].

In nonalcoholic fatty liver disease (NAFLD), Nfe2l2-mediated induction of SQSTM1 activates the noncanonical KEAP1-Nfe2l2 pathway. SQSTM1 induces ULK1 phosphorylation, leading to autophagy induction, KEAP1 degradation, and Nfe2l2 activation, which confers hepatoprotection against lipotoxicity in sqstm1-knockout mice [1]. In neuropathic pain, impaired autophagy reduces the protective effect of astrocytes on neurons against ROS stress due to decreased glutathione release, and this can be improved by activating the Nfe2l2 pathway. Moreover, simultaneous activation of autophagy and the Nfe2l2 pathway further relieves pain [2].

In conclusion, Nfe2l2 is essential for cellular antioxidant responses and maintaining cell homeostasis. Gene-knockout mouse models have revealed its significant role in diseases like NAFLD and neuropathic pain. Understanding the function of Nfe2l2 through these models provides valuable insights into the underlying mechanisms of these diseases, which may potentially lead to the development of new treatment strategies.