Crosstalk Between Sickle Cell Disease and Ferroptosis

Sickle cell disease (SCD) is an inherited hemoglobin disorder that is widespread
across the globe. It is characterized by a very complex pathogenesis, but at the basis of the
disease is the mutation of the HBB gene, which determines the production of a mutated
hemoglobin: sickle cell hemoglobin (HbS). The polymerization of HbS, which occurs when
the protein is in a deoxygenated state, and the greater fragility of sickle cell red blood cells
(sRBCs) determine the release of iron, free heme, and HbS in the blood, favoring oxidative
stress and the production of reactive oxygen species (ROS). These features are common to
the features of a new model of cell death known as ferroptosis, which is characterized by
the increase of iron and ROS concentrations and by the inhibition of glutathione peroxidase
4 (GPx4) and the System Xc−. In this context, this review aims to discuss the potential
molecular and biochemical pathways of ferroptosis involved in SCD, aiming to highlight
possible tags involved in treating the disease and inhibiting ferroptosis