Common G6PD genetic variants, particularly the African A− (V68M/N126D) and Mediterranean (S188F) alleles, reduce red blood cell transfusion efficacy through variant-specific protein instability mechanisms—kinetic fragility for A− and thermodynamic fragility for Mediterranean—that impair pentose phosphate pathway flux, increase oxidative stress during storage, and result in 8-12% lower post-transfusion recovery with measurable reductions in hemoglobin increments and end-organ oxygenation in both animal models and sickle cell disease patients.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy, affects 6% of the global population, yet its impact on blood storage and transfusion efficacy remains undefined. We integrated genome–metabolome–proteome analyses of 13,091 blood donors (362 G6PD SNPs), validated in a recalled cohort (n=643), linked donor–recipient databases, humanized mouse models (canonical, African A− [V68M+N126D], Mediterranean [S188F]), and a prospective sickle cell disease study. Common G6PD variants reduced protein abundance, reprogrammed redox metabolism, and increased storage hemolysis. In mice, G6PD-deficient RBCs showed lower post-transfusion recovery, higher oxidative stress, and impaired renal oxygenation. Clinically, recipients of G6PD-deficient units exhibited smaller hemoglobin increments and reduced RBC L¹Cr-survival (−8% at 24 h; −12% at 4 weeks). Structural studies revealed kinetic fragility for A− and thermodynamic fragility for Med−, linking genotype to protein instability and transfusion outcome. These findings identify donor G6PD genotype as a determinant of transfusion efficacy, supporting genotype-aware inventory-management strategies.