Targeted protein degradation for fetal hemoglobin induction: a new paradigm in β-hemoglobinopathy therapy.

β-Hemoglobinopathies, such as β-thalassemia and sickle cell disease, are a group of genetic blood disorders that are prevalent worldwide. These conditions are characterized by defective adult hemoglobin arising from β-globin gene mutations, leading to complications such as anemia and organ damage. Treatments (e.g., pharmaceutical γ-globin inducers, blood transfusions, stem cell transplants) and curative gene therapies are available to treat these disorders. However, their use is constrained by effectiveness, tolerability, and/or substantial resource demands. Targeted protein degraders (TPDs) are therapeutic modalities that harness cellular degradation pathways to eliminate disease‑relevant proteins, encompassing both small‑molecule approaches such as PROTACs and molecular glues, and emerging antibody- and nanobody-based degraders, with the potential to provide durable treatment with scalable manufacturing. Many TPDs for β-hemoglobinopathies target transcription factors known to repress γ-globin, thereby increasing fetal hemoglobin, a hemoglobin subtype that exhibits compensatory properties. This review examines the various γ-globin-inducing TPDs currently in development, their respective advantages and limitations. We also explore TPDs’ mechanisms of actions and emerging tools that could guide future research and development.