Fig. 3: Red blood cell phenotype of G6PD-d and potential related mechanisms to explain increased CVD.

G6PD-d can lead to both intravascular and extravascular red blood cell (RBC) destruction. a Although minimal, acute intravascular hemolysis can occur when G6PD-d individuals consume pro-oxidant medications or potentially due to chronic pro-oxidant stressors such as hyperlipidemia. Hemolysis releases heme and iron into the intravascular space. Free heme can chelate NO, thereby reducing bioavailable NO, and can directly generate powerful reactive nitrogen species (ONOO^-, peroxynitrite). Together, these can worsen VEC oxidative stress as well as the NO-depleted phenotype previously discussed (vasoconstriction, vascular permeability, leukocyte adhesion, VSMC proliferation, LDL clearance). b Extravascular destruction of oxidatively-damaged RBCs by the reticuloendothelial system accounts for a majority of RBC destruction in G6PD-d. Increased vascular permeability due to NO-depletion may increase RBC infiltration into the vascular endothelium where RBCs are further oxidized (oxRBC). Macrophage (Mφ) consumption of oxRBCs and subsequent iron overload may lead to foam cell formation as well as inflammatory Mφ formation with associated proinflammatory cytokine secretion. c Free iron exposure (VEC) and oxRBC consumption may increase cellular propensity for ferroptosis. Ferroptosis is an iron-dependent form of cell death, mediated by the formation of polyunsaturated fatty acid (PUFA) lipid peroxides, that has been linked to atherogenesis. Additionally, G6PD acts as an important mediator of cellular defenses against ferroptosis by regenerating GSH and glutathione peroxidase 4 (GPX4). G6PD-d may thereby hinder anti-ferroptotic mechanisms.