Mechanism of oxidative stress, ineffective erythropoiesis and hemolysis in β-thalassemia. Impaired α- to β-globin ratio results in aggregation and precipitation of the excess α-globin, exerting oxidative stress on the developing RBC. Concurrently, α-globin aggregates induce the sequestration of HSP70 in the cytoplasm, GDF activation and phosphorylation of SMAD2/3, and activation of SMAD4. Both processes lead to reduced GATA1 resulting in eryptosis. RBCs that exit the marrow soon undergo hemolysis because of shortened RBC lifespan. Modified from Longo F, Piolatto A, Ferrero GB, Piga A. Int. J. Mol. Sci. 2021, 22, 7229, Taher A and Saliba AN. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):265-271; Musallam KM, et al. Haematologica. 2011;96(11):1605-1612; Rivella S. Haematologica. 2015;100(4):418. ATP, adenosine triphosphate; EPO, erythropoietin; ERFE, erythroferrone; GDF, growth differentiation factor; HIF2α, hypoxic inducible factor 2α; HSP70, Heat Shock Protein 70; RBC, red blood cell; ROS, reactive oxygen species; XPO-1, exportin-1.