# The Progress in Treatment of \(\beta\)-Thalassemia and Research on Animal Models of the Disease
## 3 Treatment Approaches for \(\beta\)-Thalassemia
### Regulation of Iron Overload  
The mechanisms that regulate iron homeostasis in the human body involve the recycling of Fe\({}^{3+}\) in hemoglobin and the absorption of iron by the intestine [23]. Macrophages in the bloodstream recycle iron, and the excess iron is stored in liver cells, where it regulates the production of hepcidin. Intestinal iron absorption occurs through the collaborative action of ferroportin (Fpn) and hephaestin (Hp), which release iron into the bloodstream, where it is involved in the formation of hemoglobin (Hb) via a reduction reaction [24]. This intricate regulation ensures the balance of iron in the body and supports the proper progression of physiological processes, including normal red blood cell production. Hepcidin (HJV) is expressed in the liver, skeletal muscles, and heart and is released into the bloodstream as soluble hepcidin (sHJV). It regulates iron absorption and release by inhibiting the synthesis of ferroportin [25]. Studies have shown that children who undergo hematopoietic cell transplantation (HCT) have lower serum levels of sHJV, which are linked to the development of iron overload. It is speculated that decreased sHJV levels may result in a reduced synthesis of hepcidin, leading to increased iron absorption and storage. These findings highlight the potential role of sHJV in regulating iron metabolism [26].  
Ineffective erythropoiesis and hypoxia result in decreased hepcidin levels, increased erythropootin production, and activation of the intestinal HIF-\(\alpha\) pathway. The liver regulates iron absorption through the hepcidin/intestinal HIF-\(\alpha\) axis, modulating the physiological iron intake in response to systemic iron deficiency. Conversely, in conditions of iron overload, this mechanism may elicit pathological iron absorption, ultimately resulting in iron overload in individuals with \(\beta\)-thalassemia [27].  
Currently, clinical treatments for iron overload include iron chelation therapy, enhancement of the hepcidin levels, and regulation of iron transport proteins. The iron chelators commonly used in clinical practice primarily include desferrioxamine (DFO), deferiprone (DFP), and deferasirox (DFX) [28]. Research indicates that hepcidin binds to the membrane iron transporter and induces its degradation, which inhibits iron absorption and recycling, thus exacerbating iron metabolism disorders in thalassemia patients [29]. VIT-2763, a novel oral small molecule inhibitor of iron transport proteins, effectively blocks iron efflux within cells by competing with hepcidin for binding to Fpn, thereby promoting Fpn internalization and ubiquitination. Experimental results demonstrate that VIT-2763 significantly alleviates anemia in Hbb\({}^{\text{th3}}\) mice, enhances ineffective erythropoiesis, reduces ROS levels, mitigates oxidative damage, and decreases hepatic iron overload [30]. Transferrin receptor 2 (TFR2) acts as an activator of hepcidin in the liver and regulates erythropoogentin signaling in erythrocytes. The absence of bone marrow (BM) Tfr2 alleviates anemia and ineffective erythropoiesis, partially mitigating hepatic iron overload in the Hbb\({}^{\text{th3}}\) mouse model [31]. Furthermore, it downregulates the gene of the hepcidin inhibitor TMPRSS6, thereby enhancing this effect [27].  
In summary, significant advancements have been made in the development of targeted therapies for \(\beta\)-thalassemia, such as PK-R activators and Fpn inhibitors [22]. These therapies go beyond merely promoting \(\gamma\)-globin gene transcription or enhancing fetal hemoglobin (HbF) synthesis; they also improve the severity of anemia in \(\beta\)-thalassemia through various mechanisms, targets, and pathways. This reflects an enhanced understanding of the pathogenesis of \(\beta\)-thalassemia and supports more targeted treatment approaches. Future clinical trials are critical for investigating the dosage, efficacy, adverse effects, and combination therapy strategies of these new drugs, aiming to achieve better outcomes for patients with \(\beta\)-thalassemia.