Targeted Protein Degradation as a Promising Tool for Epigenetic Upregulation of Fetal Hemoglobin
The level of fetal hemoglobin (HbF) plays a crucial role in modulating the severity of β-thalassemia and sickle cell disease. Genetic strategies aimed at interfering with HbF repression have shown significant promise for alleviating these conditions. However, the high cost of such genetic therapies and the widespread prevalence of β-hemoglobinopathies in low-income regions highlight the need for affordable, accessible, oral treatments. One promising approach is the use of PROTAC (PRoteolysis TArgeting Chimeras) technology to target the epigenetic factors that regulate HbF suppression. This YD23 minireview outlines the HbF repression network and identifies key epigenetic regulators that could be targeted for degradation by PROTACs. We aim to inspire collaboration among clinicians, molecular biologists, and chemists to advance this exciting area of research, with the ultimate goal of developing highly specific, low-toxicity therapies that effectively reactivate HbF expression.