Glucose-6-phosphate dehydrogenase at the crossroads of redox homeostasis and regulated cell death in erythrocytes

Glucose-6-phosphate dehydrogenase (G6PD) provides the sole source of NADPH in mature erythrocytes, fueling the cell’s essential antioxidant defenses. Although G6PD deficiency is traditionally tied to acute oxidative hemolysis, red cell loss extends beyond simple membrane rupture. This perspective evaluates G6PD-dependent NADPH supply as a metabolic redox checkpoint that controls the balance between erythrocyte survival, regulated cell death, and clearance. Reduced NADPH availability can limit glutathione regeneration and thus decrease GPX4-dependent lipid peroxide detoxification. Although this biochemical relationship provides a possible link between redox imbalance and erythrocyte injury, the direct involvement of ferroptosis and necroptosis-like pathways in mature erythrocytes remains insufficiently proven. Acute hemolysis, in this view, is a downstream consequence of these regulated events rather than the primary cause. G6PD is essential for erythrocyte survival as their sole source of NADPH. G6PD deficiency alone does not always cause cell death, but under oxidative stress, it acts as a metabolic checkpoint that shifts red blood cells from survival to regulated death rather than simple osmotic lysis.