HBB encodes hemoglobin subunit beta, a critical component of adult hemoglobin responsible for oxygen transport and binding 1. Beyond its canonical respiratory function, HBB serves as an endogenous inhibitor of enkephalin-degrading enzymes and acts as a selective antagonist of the P2RX3 pain signaling receptor, implicating it in pain and inflammation regulation. The gene is essential for erythrocyte development and functions within the hemoglobin complex alongside alpha-globin subunits. HBB mutations cause severe monogenic blood disorders affecting millions globally. Over 200 different mutations have been identified, with approximately 20 alleles responsible for >80% of cases 2. The most common disease associations include sickle cell disease, caused by the Glu6Val mutation (c.20T>A), which arose from a single African origin and confers malaria resistance 3. Beta-thalassemia results from various loss-of-function mutations; the CD41-42 (-TCTT) deletion represents the most prevalent mutation in China and Southeast Asia 4. Clinical severity correlates with specific mutations 2. Gene-editing approaches using CRISPR/Cas9 and adenine base editors have demonstrated preclinical efficacy for correcting HBB mutations in patient-derived hematopoietic stem cells, offering potential one-time curative therapies 564.