Understanding how mechanical stress affects erythropoiesis is crucial to produce transfusable erythrocytes in fluid-turbulent bioreactors. We investigated the effects of shear-stress on differentiating CD49d+CD235a+ primary human erythroblasts (EBL) at molecular, cellular, and functional level. Shear-stress, at differentiation onset, enhanced EBL maturation and induced upregulation of genes regulating cholesterol/lipids biosynthesis, causing changes in cell lipid composition. Of note, the osmotic resistance, and the expression of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthesis pathway, were higher in dynamic cultures. Inhibition of the S1P-induced proteolytic cleavage, activating SREBPs, led to abrogation of HMCGR expression, and loss of EBL in dynamic cultures, similar to lovastatin administration. This data reveals a role for the S1P-SREBP-HMGCR-axis in the regulation of shear-stress induced adaptation during erythropoiesis, shedding light into mechanisms that will assist the upscaling of erythroid differentiation into bioreactors. Moreover, as shear-stress on hematopoietic cells occurs within the bone-marrow, these results introduce a novel signalling axis in the transduction pathways controlling erythropoiesis.