Ineffective erythropoiesis, the main cause of anemia in β-thalassemia disease, is characterized by dramatic
expansion of erythroblasts and increased erythroblast cell death. The absence or reduction of β-globin chains
causes an accumulation of excess α-globin chains and generates cytotoxic reactive oxidant species, resulting in
erythroblast cell death. Metabolism provides energy, building blocks for macromolecule synthesis, and cofactors
for antioxidative defense systems. We hypothesized that β-thalassemia erythroblasts might alter their metabolism
to cope with increased proliferation and cellular stress. Herein, transcriptomic analysis of basophilic and polychromatic erythroblasts isolated from bone marrow obtained from β-thalassemia/HbE patients showed the global
up-regulation of metabolic genes in glycolysis, TCA cycle, pentose phosphate pathway, ATP, and fatty acid
synthesis pathway. The expression of metabolic genes during terminal erythropoiesis was further determined by
PCR array and RT-qPCR in erythroblast culture obtained from β-thalassemia/HbE patients with mild and severe
symptoms. The increased expression of enolase1, isocitrate dehydrogenase 1, and bisphosphoglycerate mutase
was observed in mild cases compared to severe patients, suggesting that mild patients might modulate metabolic
flux for cellular stress defense mechanisms, reducing disease severity. Moreover, the role of BPGM in regulating
erythroid differentiation was demonstrated in K562 cells. Inhibition of BPGM promotes cell differentiation in
K562 cells. Understanding metabolic reprogramming in thalassemia erythropoiesis opens new therapeutic approaches for β-thalassemia/HbE treatment. Further research is needed to explore how metabolism affects ineffective erythropoiesis and supports thalassemic erythroblasts’ high proliferation and oxidative stress defense.

Keywords: Metabolic reprogramming, Metabolic genes, Metabolism, Ineffective erythropoiesis, В-Thalassemia/HbE disease