Trsp^−/− mice mimic aged hematopoiesis with impaired HSC function and B-cell development, accompanied with enhanced myeloid skewing. Balanced hematopoiesis (blue lines) involves (1) the self-renewal of HSCs and (2) the differentiation of HSCs into lymphoid cells (eg, B and T cells via lymphopoiesis) and myeloid cells (eg, neutrophils and monocytes via myelopoiesis). During aging, increased oxidative stress reduces HSC regenerative capacity and skews lineage differentiation toward myelopoiesis. Similarly, Trsp^−/− mice, with impaired selenoprotein synthesis (red lines), exhibit reduced HSC self-renewal and a blockade in B-cell maturation, where pro-B cells differentiate toward the myeloid lineage (namely neutrophils). Additionally, heightened oxidative stress promotes ferroptosis in B cells, which are inherently susceptible due to elevated levels of PUFA-PLs, whereas myeloid cells, with lower PUFA-PL levels, are relatively protected. This phenotype, mimicking aged hematopoiesis, can be partially reversed by the ferroptosis inhibitor vitamin E, which restores redox balance and prevents cell death. Figure created with BioRender.com.