Nfe2l2, also known as NRF2 (nuclear factor, erythroid 2 like 2), is a transcription factor that serves as the master regulator of cellular antioxidant responses. It is part of the KEAP1-Nfe2l2 pathway, a pivotal defense mechanism against various stressors, which is crucial for maintaining cell homeostasis. Dysregulation of this pathway has been linked to multiple diseases [1,2,3,4,5].

In the context of non-alcoholic fatty liver disease (NAFLD), lipotoxicity-induced cell death is an important pathogenic factor. In sqstm1-and liver-specific sqstm1-knockout mice, it was found that Nfe2l2-mediated induction of SQSTM1 activates the non-canonical KEAP1-Nfe2l2 pathway. SQSTM1 induces ULK1 phosphorylation, leading to autophagy induction, KEAP1 degradation, and Nfe2l2 activation, conferring hepatoprotection against lipotoxicity. This pathway was also evident in the livers of patients with non-alcoholic fatty liver, suggesting it could be a novel target for NAFLD treatment [1].

In summary, Nfe2l2 plays a central role in antioxidant defense and cell homeostasis through the KEAP1-Nfe2l2 pathway. The study of Nfe2l2 using knockout mouse models, like in the context of NAFLD, has revealed its significance in protecting against lipotoxicity, providing valuable insights into disease mechanisms and potential therapeutic targets.