Nfe2l2, also known as NRF2 (nuclear factor, erythroid 2 like 2), is a master regulator of cellular antioxidant responses. It is a key transcription factor in the KEAP1-Nfe2l2 pathway, a pivotal defense mechanism against lipotoxicity, oxidative stress, and other cellular insults [1,2,5,6]. This pathway is crucial for maintaining cell homeostasis and has implications in various biological processes and disease conditions such as non-alcoholic fatty liver disease (NAFLD), neuropathic pain, and cancer [1,2,3,4,6]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In the context of NAFLD, Nfe2l2-mediated induction of SQSTM1 activates the non-canonical KEAP1-Nfe2l2 pathway under lipotoxic conditions. SQSTM1-deficient mice, both conventional and liver-specific, showed that the SQSTM1-mediated non-canonical KEAP1-Nfe2l2 pathway confers hepatoprotection against lipotoxicity, indicating Nfe2l2's role in protecting the liver from lipotoxicity-induced damage [1]. In NSCLC, Nfe2l2 and its upstream regulator KEAP1 are frequently mutated. These mutations are associated with enhanced tumor growth, aggressiveness, and refractoriness to cancer-directed therapies. The TORC1/2 inhibitor TAK-228 shows single-agent activity in Nfe2l2-activated LUSC, suggesting potential targeted therapies [3,4].

In conclusion, Nfe2l2 plays essential roles in maintaining cellular antioxidant defenses and homeostasis. Model-based research, especially KO/CKO mouse models, has revealed its significance in diseases like NAFLD and NSCLC. Understanding Nfe2l2's functions provides insights into disease mechanisms and potential therapeutic targets for these and other related diseases.

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/