NFE2L2

NFE2L2 (Nuclear factor erythroid 2-related factor 2, also known as NRF2) is the master transcription factor regulating cellular antioxidant and cytoprotective responses. As a CNC-bZIP family member, NRF2 heterodimerizes with small MAF proteins (MAFG, MAFK, MAFF) to bind antioxidant response elements (AREs) in the promoters of target genes including phase II detoxifying enzymes (NQO1, GSTA), glutathione synthesis genes (GCLC, GCLM), heme oxygenase (HMOX1), and the cystine/glutamate antiporter SLC7A11. Under basal conditions, NRF2 is sequestered in the cytoplasm by KEAP1, which serves as a substrate adaptor for the CUL3-RBX1 E3 ubiquitin ligase complex, targeting NRF2 for proteasomal degradation with a half-life of approximately 15 minutes. Upon oxidative stress or electrophile exposure, reactive KEAP1 cysteines are modified, disrupting NRF2 ubiquitination and allowing newly synthesized NRF2 to accumulate in the nucleus. NRF2 also plays a critical role in protection against ferroptosis by inducing genes that maintain iron and lipid homeostasis. Constitutive NRF2 activation via somatic mutations in NFE2L2 or KEAP1 is common in lung cancers and promotes tumor progression and therapy resistance.

Disorders

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