Nfe2l2, also known as NRF2 (nuclear factor, erythroid 2 like 2), is a master regulator of cellular antioxidant responses. It is a transcription factor that plays a pivotal role in upregulating anti-ferroptotic defense [5]. The KEAP1-Nfe2l2 pathway is a key defense mechanism against lipotoxicity, and Nfe2l2 is repressed by interaction with the redox-sensitive protein KEAP1 [1,6]. Dysregulation of this pathway is associated with the pathogenesis of multiple diseases, including non-alcoholic fatty liver disease (NAFLD), neuropathic pain, and various cancers [1,2,3,4,6]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In the context of NAFLD, in conventional sqstm1-and liver-specific sqstm1-knockout mice, activation of the noncanonical KEAP1-Nfe2l2 pathway by SQSTM1/p62 protected the liver from lipotoxicity. SQSTM1 induced ULK1 phosphorylation, leading to autophagy induction, KEAP1 degradation, and Nfe2l2 activation [1]. In NSCLC, Nfe2l2-activating alterations were targeted by the TORC1/2 inhibitor TAK-228, which showed efficacy in a LUSC cohort with Nfe2l2 alterations [3]. Mutations in the KEAP1-Nfe2l2 pathway in NSCLC have been associated with refractoriness to cancer-directed therapies [4].

In conclusion, Nfe2l2 is crucial for maintaining cellular redox balance and antioxidant defense. Model-based research, especially KO/CKO mouse models, has revealed its role in diseases like NAFLD and NSCLC. Understanding Nfe2l2 functions provides potential therapeutic targets for these diseases. [1,3,4]

References:

1. Lee, Da Hyun, Park, Jeong Su, Lee, Yu Seol, Lee, Yong-Ho, Bae, Soo Han. 2020. SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. In Autophagy, 16, 1949-1973. doi:10.1080/15548627.2020.1712108. https://pubmed.ncbi.nlm.nih.gov/31913745/

2. Li, Jian, Tian, Mouli, Hua, Tong, Zhang, Xiaoping, Yuan, Hongbin. 2021. Combination of autophagy and NFE2L2/NRF2 activation as a treatment approach for neuropathic pain. In Autophagy, 17, 4062-4082. doi:10.1080/15548627.2021.1900498. https://pubmed.ncbi.nlm.nih.gov/33834930/

3. Paik, Paul K, Fan, Pang-Dian, Qeriqi, Besnik, de Stanchina, Elisa, Rudin, Charles M. 2022. Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 18, 516-526. doi:10.1016/j.jtho.2022.09.225. https://pubmed.ncbi.nlm.nih.gov/36240971/

4. Hellyer, Jessica A, Padda, Sukhmani K, Diehn, Maximilian, Wakelee, Heather A. 2020. Clinical Implications of KEAP1-NFE2L2 Mutations in NSCLC. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 16, 395-403. doi:10.1016/j.jtho.2020.11.015. https://pubmed.ncbi.nlm.nih.gov/33307193/

5. Tang, Daolin, Chen, Xin, Kang, Rui, Kroemer, Guido. 2020. Ferroptosis: molecular mechanisms and health implications. In Cell research, 31, 107-125. doi:10.1038/s41422-020-00441-1. https://pubmed.ncbi.nlm.nih.gov/33268902/

6. Dempke, Wolfram C M, Reck, Martin. 2021. KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype? In Lung cancer (Amsterdam, Netherlands), 159, 10-17. doi:10.1016/j.lungcan.2021.07.006. https://pubmed.ncbi.nlm.nih.gov/34303275/