Cellular and molecular targets in β-Thalassemia: advances in iron Regulation, Erythropoiesis, and Gene-Based therapies.

β-Thalassemia is a prevalent autosomal recessive genetic disorder caused by mutations in the β-globin gene, leading to impaired hemoglobin production and chronic anemia. While traditional treatments such as regular blood transfusions, iron chelation, and supportive care have significantly improved patient survival, these methods remain palliative. The availability of curative options is limited, with allogeneic hematopoietic stem cell transplantation (HSCT) presenting risks due to donor constraints and procedure-related complications. Recent advances in the molecular understanding of β-thalassemia have opened the door to novel therapeutic strategies. Gene therapy approaches, including lentiviral vector-mediated β-globin gene addition and CRISPR/Cas9-mediated genome editing targeting the BCL11A enhancer, have shown promising results in clinical trials and have gained regulatory approval in several regions. Pharmacological interventions, such as luspatercept, which enhances erythroid maturation, and other fetal hemoglobin inducers, offer valuable alternatives for patients who are ineligible for gene-based therapies. This review explores the current landscape of β-thalassemia, including its epidemiology, pathophysiology, and clinical manifestations, while highlighting recent advances in treatment options. We critically evaluate the clinical data emerging from gene therapies and other innovative treatments, address the ongoing challenges, and outline future directions for enhancing patient outcomes through personalized and accessible care strategies.