pQTL analysis identifies a cis-mapping region on chromosome 19 for GPX4. Protein levels at storage days 10, 23, and 42 for GPX4 were used as quantitative trait, and mapped against 879 000 SNPs that were assayed in the REDS RBC Omics donors (A). The analysis identified a cis region on chromosome 19 mapping on the gene coding for GPX4 (Manhattan plot and LocusZoom; B-C). (D-E) LDA of integrated multiomics data in REDS recalled donors based on rs73207255 (missense) or rs8178977 (higher GPX4 protein levels), either unadjusted (x-axis), or adjusted by storage day, additive, donor sex, age, and body mass index (y-axis). (F) GPX4 protein levels correlated (Spearman) to allele frequency for GPX4 SNPs and omics parameters. Based on established kinetics for GPX4-dependent detoxification of lipid hydroperoxides to lipid alcohols (G), optimizations of the proteome-constrained RBC-GEM revealed flux through the glutathione peroxidase reaction (GTHP) decreased linearly with respect to GPX4 abundance (H), resulting in decreased peroxide detoxification and increased lipid hydroperoxide formation. Other proteins with lipid hydroperoxide glutathione peroxidase activity (ie, glutathione peroxidase [GPX1] and periredoxin 6 [PRDX6]) can compensate for the loss of GPX4; however, the cell’s overall capacity to detoxify hydroperoxides diminished after ∼70% GPX4 reduction (I).