Figure 6. Schematic diagram of the downstream effects on β-thalassemic erythroblasts when glycine uptake is impaired by bitopertin, a specific inhibitor of the GlyT1 transporter.

Bitopertin modulates heme biosynthesis, which affects the amount of free heme (in the in vitro model of human erythropoiesis, we observed a reduction of protoporphyrin IX). This results in reduction of oxidative stress with associated decrease in activation of HRI, which orchestrates eIF2α and senses free heme concentration. The optimization between heme and α-globin chain synthesis further contributes to the reduction in generation of ROS, resulting in the blockage of mTOR and activation of autophagy, which contributes to the clearance of damaged proteins, assisting β-thalassemic cell survival during growth and maturation.