Missense GPX4 SNPs are associated with lower hemoglobin increments in transfusion recipients. Interrogation of a vein-to-vein database including thousands of transfusion recipients revealed that donors carrying the rs73507255 missense allele were characterized by lower hemoglobin increments at 24 hours upon transfusion, especially when the units transfused ranked on quartile 2nd or higher by storage age (A-C). Given the prevalence of GPX4 missense SNPs in donors of African descent (see Figure 3), we also identified a subset of donors carrying 2 alleles (homozygous recessive) of the GPX4 missense SNP who were also G6PD deficient (African variant). However, the effects of the 2 traits did not compound with respect to the impact on hemoglobin increments (driven by GPX4 in this subanalysis; D) or glutathione levels (driven by G6PD status in this subanalysis; E). LDA of REDS recalled multiomics data by GPX4 status, unadjusted (x-axis) or adjusted by G6PD status (y-axis), identified a strong impact of either trait on the related protein levels (F), with a combined effect on nucleotide and cholesterol metabolism, PPP and glutathione metabolism, vesiculation (endo/exocytosis) and ubiquitination (G). Focusing on the proteome, the combined effect of the 2 traits identified a network of interacting proteins involved in proteasomal degradation (H), consistent with a model (I) positing the upregulation of damaged proteins via ubiquitination and proteasomal degradation in the context of genetic traits impairing both prevention of oxidant stress (ie, G6PD deficiency) or repair of the oxidant damage to lipids (GPX4 missense mutations).