Oridonin enhances γ‑globin expression in erythroid precursors from patients with β‑thalassemia via activation of p38 MAPK signaling.

Upregulation of fetal hemoglobin expression can alleviate the severity of beta-thalassaemia. This study aimed to investigate the effects of Oridonin (ORI, a diterpenoid compound) on gamma-globin expression in human erythroid precursor cells and the potential underlying mechanisms. Erythroid precursor cells were enriched from 12 patients with beta-thalassaemia by two-phase culture. The cells were then treated with different doses of ORI and the survival of erythroid precursor cells was determined. In addition, the expression levels of gamma-globin and potential mechanisms were analyzed by reverse transcription-quantitative PCR, western blotting and chromatin immunoprecipitation. Treatment with 0.5 mu M ORI preferably enhanced gamma-globin expression and exhibited little cytotoxicity. Similar to sodium butyrate (NaB, a histone deacetylase inhibitor), ORI significantly increased p38 mitogen-activated protein kinase (MAPK) activation, gamma-globin expression, histone H3 and H4 acetylation at the G gamma- and A gamma-globin promoters, and cAMP-response element binding protein 1 (CREB1) phosphorylation. These effects were significantly mitigated by treatment with SB23580, a p38 MAPK inhibitor, in erythroid precursor cells. Therefore, ORI may effectively enhance gamma-globin expression by activating p38 MAPK and CREB1, leading to histone modification in gamma-globin gene promoters during the maturation of erythroid precursor cells. These findings suggested that ORI may be a novel and potential therapeutic agent for the treatment of beta-thalassaemia.