Sickle cell disease (SCD) is a monogenic inheritable disease characterized by severe
anemia, increased hemolysis, and recurrent, painful vaso-occlusive crises due to the
polymerization of hemoglobin S (HbS)-generated oxidative stress. Up until now, only four
drugs are approved for SCD in the US. However, each of these drugs affects only a limited
array of SCD pathologies. Importantly, curative therapies, such as gene therapy, or
hematopoietic stem cell transplantation are not available for every patient because of their …

SCD sequelae. SCD phenotypic severity can be alleviated by increasing fetal hemoglobin
(HbF) expression. This results in the inhibition of HbS polymerization and thus sickling, and
a reduction in oxidative stress. The efficacy of HbF is due to its ability to dilute HbS levels
below the threshold required for polymerization and to influence HbS polymer stability in
RBCs. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)-
complex signaling is one of the most important cytoprotective signaling controlling oxidative …