NFE2L2 (NRF2) is a master transcription factor that regulates cellular responses to oxidative stress and maintains cellular homeostasis. Under normal conditions, NFE2L2 is regulated by KEAP1-mediated ubiquitination and proteasomal degradation in the cytoplasm 1. Upon oxidative stress, NFE2L2 translocates to the nucleus where it binds to antioxidant response elements (AREs) and activates expression of cytoprotective genes including antioxidant enzymes and detoxification proteins 2. NFE2L2 plays a central role in preventing ferroptosis by upregulating glutathione synthesis enzymes GCLM and GCLC, with glutathione subsequently transported into mitochondria via SLC25A39 to chelate copper and prevent cuproptosis 34. The transcription factor exhibits dual roles in disease: it provides cellular protection against environmental insults in normal cells, but constitutively elevated levels in certain cancers promote tumor survival, progression, and therapy resistance 2. In esophageal squamous cell carcinoma, NFE2L2 mutations are associated with worse prognosis, suggesting it may function as a tumor suppressor in this context 5. Therapeutic targeting of the NFE2L2-KEAP1 pathway shows promise for treating chr2 diseases, with one NRF2 activator already clinically approved 1.