Crosstalk Between Sickle Cell Disease and Ferroptosis

Abstract

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.

Keywords: GPx4; cell death; iron overload; oxidative stress; sickle cell hemoglobin; system Xc−; transfusion.

Figure 1

Pathophysiology of sickle cell disease. The image shows the gradual change in erythrocytes in SCD and the potential pathophysiological events that may be triggered due to the disease. Mutated HbS, under low oxygen pressure, tends to polymerize, increasing the fragility of sRBCs and promoting their lysis (normal RBC on the left and sickle cell on the right). This condition triggers an increase in HbS and iron in the bloodstream, contributing to the cascade of processes involved in the disease, such as oxidative stress, inflammation, endothelial dysfunction, etc.

Figure 2

Implications of Ferroptosis in SCD. Hb auto-oxidation and erythrocyte hemolysis, two of the main features of SCD, and transfusions contribute to the accumulation of iron and heme in the blood. This condition, on the one hand, promotes the Fenton reaction leading to radical production, and on the other hand, promotes the activation of enzymes involved in radical production, such as lipoxygenase, NOX1, HO-1, etc. This leads to the accumulation of ROS, increased lipid peroxidation, and stimulation of ferroptosis.