Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease

Individuals with sickle cell disease have severe anemia due to the production of abnormal hemoglobin S, chronic red blood cell hemolysis, and increased oxidative stress leading to endothelial cell dysfunction, vasculopathy, and progressive organ damage. The transcription factor NRF2 (erythroid-derived 2)-like 2) is a master regulator of antioxidant proteins; under low oxidative stress, NRF2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, β-transducin repeat-containing protein or HRD1, and directed to the proteasome for degradation. When cells are exposed to oxidative stress, NRF2 is released from these repressor proteins, translocates to the nucleus, and activates antioxidant genes to suppress cellular reactive oxidant species and inflammation. In erythroid progenitors, NRF2 also modulates fetal hemoglobin expression through direct binding in the γ-globin promoter and modification of chromatin structure in the β-globin locus. In sickle erythroid cells, NRF2 provides unique benefits...