HBG2 encodes the gamma-2 globin chain, a component of fetal hemoglobin (HbF, α2γ2) that is normally silenced after birth and replaced by adult hemoglobin (HbA, α2β2) 1. HBG2 functions as an oxygen carrier through heme binding and participates in oxygen and carbon dioxide transport within erythrocytes. The developmental silencing of HBG2 involves multiple regulatory mechanisms: NFI transcription factors (NFIA and NFIX) repress HBG2 partly by inducing BCL11A expression and through direct repression 2, while CpG methylation at the HBG2 promoter maintained by UHRF1 also facilitates gene silencing 3. HBG2 reactivation has major therapeutic potential for β-hemoglobinopathies. Multiple genome-editing approaches successfully reactivate HBG2 expression: HIF1α stabilization induces γ-globin transcription through BGLT3 1, adenine base editors achieve up to 60% editing efficiency at HBG2 promoter variants 4, and a single nucleotide insertion in the HBG2 distal promoter creates a FOXO3 binding site to increase expression 5. Clinical studies demonstrate that genetic variants in HBG2 significantly associate with fetal hemoglobin levels and sickle cell disease severity 6. These findings establish HBG2 reactivation as a promising therapeutic strategy for treating sickle cell disease and β-thalassemia.