The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia

Abstract

In Guangxi, Hainan, and Fujian Province in southern China, β-thalassemia is a frequent monogenic hereditary disorder that is primarily defined by hemolytic anemia brought on by inefficient erythropoiesis. It has been found that ineffective erythropoiesis in β-thalassemia is closely associated with a high accumulation of Reactive oxygen species, a product of oxidative stress, in erythroid cells. During recent years, ferroptosis is an iron-dependent lipid peroxidation that involves abnormalities in lipid and iron metabolism as well as reactive oxygen species homeostasis. It is a recently identified kind of programmed cell death. β-thalassemia patients experience increased iron release from reticuloendothelial cells and intestinal absorption of iron, ultimately resulting in iron overload. Additionally, the secretion of Hepcidin is inhibited in these patients. What counts is both ineffective erythropoiesis and ferroptosis in β-thalassemia are intricately linked to the iron metabolism and Reactive oxygen species homeostasis. Consequently, to shed further light on the pathophysiology of β-thalassemia and propose fresh ideas for its therapy, this paper reviews ferroptosis, ineffective erythropoiesis, and the way they interact.

Keywords: ROS; ferroptosis; ineffective erythropoiesis; iron overload; pathogenesis; β-thalassemia.

FIGURE 1

Regulation mechanisms of differentiation and maturation of erythroid cells in, IE. The maturation of erythrocytes needs to go through hematopoietic stem cells, erythroid progenitor cells, erythroid precursor cells, and erythrocytes stages. As shown in the figure, when, IE occurs, various stages of differentiation and maturation of erythroid cells are respectively affected by several molecular mechanisms. Moreover, ROS homeostasis is in a key position in the occurrence of, IE, which connects the molecular mechanisms at each stage. (Abbreviations: BFU-E, burst-forming unit-erythroid; CFU-E, colony forming unit-erythrocyte; HIF α2, hypoxia-inducible factorα2; EPO, Erythropoietin; AHSP, α-hemoglobin stabilizing protein; HbA1, hemoglobin A1; HSP70, heat shock protein 70; ROS, reactive oxygen species; GDF11, 15, growth differentiation factor 11,15; ActRIIA, ActRIIB, activation of activin receptors IIA, IIB).

FIGURE 2

Mechanisms of ferroptosis in β-thal and occurrence and regulation of ferroptosis. Ferroptosis in β-thal is thought to be caused by excessive iron-dependent ROS production, and it is driven by iron-dependent lipid peroxidation. Therefore, ferroptosis is characterized by an imbalance in iron homeostasis and ROS homeostasis. It is interesting to note that mitochondria are crucial for controlling ROS homeostasis. Moreover, system Xc⁻, Nrf2, and GPX4 are the primary regulators of ferroptosis. (Abbreviations: VDAC, voltage-dependent anion channel; ROS, reactive oxygen species; GSSH, oxidized glutathione; GSH, glutathione; Nrf2, nuclear factor erythroid 2-related factor 2; GPX4, glutathione peroxidase 4; LPCAT3, lysophosphatidylcholine acyltransferase-3; ACSL4, Acyl-CoA synthetase long-chain family member 4; β-thal, β-thalassemia; TCA, tricarboxylic acid cycle).