Chumchuen S.Pornsukjantra T.Innachai P.Khamphikham P.Wongborisuth C.Anurathapan U.Songdej D.Sripichai O.Tangprasittipap A.Hongeng S.Mahidol University2025-12-292025-12-292025-12-01Scientific Reports Vol.15 No.1 (2025)https://repository.li.mahidol.ac.th/handle/123456789/113694Zinc finger and BTB domain-containing 7A (ZBTB7A) is a transcription factor repressor of fetal hemoglobin (HbF; α<inf>2</inf>γ<inf>2</inf>) in erythroid cells. Reactivating γ-globin expression represents a promising therapeutic strategy for β-hemoglobinopathies, including β-thalassemia. While ZBTB7A knockdown is known to elevate HbF levels in HUDEP-2 erythroid cell line and human hematopoietic stem/progenitor cell (HSPC)-derived erythroblasts, its effects in patient-derived cells remain less defined. This study investigates the effects of ZBTB7A downregulation in erythroid cells derived from both β⁰ thalassemia/hemoglobin E (β⁰-thal/HbE) patients and healthy donors. ZBTB7A knockdown upregulated embryonic and fetal globin genes (ε-, ζ-, γ-globin), and robust HbF induction while suppressing adult globin gene expression (α-, β-, δ-globin) in both groups. Notably, partial ZBTB7A inhibition was sufficient to achieve HbF reactivation. ZBTB7A depletion delayed erythroid maturation in healthy cells, but not in β⁰-thal/HbE cells, revealing a context-dependent effect on differentiation. These findings support ZBTB7A as a compelling target for β-thalassemia therapy, where partial inhibition could potentially offer therapeutic benefit while minimizing adverse effects on erythroid differentiation.MultidisciplinaryArticleSCOPUS10.1038/s41598-025-30762-32-s2.0-1050252314632045232241345769