Model of CY561A3 and STEAP3 iron metabolism roles in Burkitt cells vs LCLs. Transferrin-bound Fe3⁺ iron is endocytosed by the transferrin receptor TFRC and delivered to lysosomes in both LCLs and Burkitt cells. Iron can also be delivered to B-cell lysosomes by ferritinophagy or by mitophagy. The acidic lysosomal microenvironment facilitates release of Fe3⁺, which is reduced for LCL cytosolic transport by STEAP3 to Fe2⁺, using NADPH as an electron donor. By contrast, Burkitt B cells with the EBV latency I program use the ferrireductase CYB561A3 to reduce Fe3⁺ to Fe2⁺, with ascorbate as the electron donor. The cytosolic labile iron pool then supplies a myriad of cellular functions, including iron-sulfur synthesis and respiration. Ferrous iron is also essential for suppression of hypoxia inducible factor 1 subunit α (HIF1α). The metallothionein MT2A binds ferrous iron, and its Burkitt cell expression is dependent on CYB561A3, presumably through an iron-dependent mechanism. In the absence of CYB561A3, Burkitt cells are rapidly depleted of labile iron; they induce an iron starvation response but nonetheless sustain catastrophic lysosomal and mitochondrial damage. LMPs, latent membrane proteins; NADP⁺, nicotinamide-adenine dinucleotide phosphate, oxidized form; ncRNAs, noncoding RNAs.