NFE2L1 (Nuclear Factor Erythroid 2-Like 1) is a CNC-bZIP transcription factor that functions as a master regulator of cellular stress responses and metabolic homeostasis 1. The protein heterodimerizes with small-Maf proteins and binds antioxidant response elements (AREs) to regulate genes involved in oxidative stress defense 1. NFE2L1 resides on the endoplasmic reticulum membrane and requires proteolytic cleavage by DDI2 and deglycosylation to translocate to the nucleus and activate target genes 23. NFE2L1 exerts multifaceted functions across three major domains: (1) redox homeostasis through induction of antioxidative response genes 1; (2) proteasome biogenesis and proteostasis, where it activates proteasomal subunit genes in response to proteotoxic stress 45; and (3) metabolic regulation, controlling glucose metabolism, lipid homeostasis, and cholesterol balance 6. In cardiac tissue, NFE2L1 activation protects against ischemia/reperfusion injury and promotes neonatal heart regeneration through dual stress response mechanisms 4. In neurodegeneration models, NFE2L1 overexpression delays photoreceptor loss by enhancing proteasomal clearance of misfolded proteins 5. Dysregulation of NFE2L1 is implicated in metabolic disorders, neurodegenerative diseases, cardiovascular disease, and cancer 16.