Schema of ROS-mediated pathophysiology and potential mechanism of drug targets in SCD. (1) Intracellular ROS in the RBC. Auto-oxidative unstable HbS, HbS polymerization, membrane-bound hemichrome, activity of NADPH oxidases, depleted antioxidants, iron-mediated Fenton reaction, and mitochondrial retention facilitate excessive ROS generation in the RBCs. (2) ROS in the intravascular lumen. RBC intravascular hemolysis abnormally activates body immune and inflammatory responses that further amplify ROS and magnify the impact on endothelial cells. Chronic inflammatory and immunological responses alter vascular dysfunction, leading to hypoxia and infarction-mediated irreversible damage in multiple organ systems. This network of ROS production can be disrupted or inhibited by the treatment of various agents. IVIG; immunoglobin IV; NAC, N-acetylcysteine.