Novel agents targeting HbF induction. HbF has the ability to interfere with HbS polymerization. DNA methyltransferases (DMNTs) modify DNA by methylation of its cytidine residues, resulting in transcriptional silencing. Decitabine inactivates DNMT1, allowing for decreased methylation of the γ-globin promoter and increased gene expression. Histone deacetylators (HDACs) remove acetyl groups, primarily from histone lysine residues, leading to a more closed chromatin configuration, which represses gene expression by reducing access to interacting regulatory proteins. Panobinostat inhibits HDACs, maintaining an open acetylated chromatin configuration of the γ-globin promoter, allowing for gene expression. INCB059872 inhibits LSD1, an inhibitor of HbF production, as well as prevents ROS accumulation in RBCs. Metformin induces FOXO3, a transcription factor that upregulates HbF production, although the precise mechanism of the effect of metformin on HbF induction is still being elucidated.