Noncoding RNA-Mediated Control of HbF Switching: From Molecular Mechanisms to Clinical Translation

Abstract

Noncoding RNAs (ncRNAs) act as critical epigenetic regulators of fetal hemoglobin (HbF) switching, offering new therapeutic possibilities for treating β-hemoglobinopathies, including sickle cell disease and β-thalassemia. Despite significant advances, the exact role of ncRNA-mediated regulatory networks within existing models of transcriptional and epigenetic regulation of γ-globin expression remains unclear. This review summarizes the roles and interplay of microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs) in controlling γ-globin expression, along with their interactions with key regulators such as BCL11A, KLF1, and various epigenetic modifiers. miRNAs, including miR-15a, miR-16-1, miR-486-3p, and miR-210, have been found to regulate key transcription factors that act as either enhancers or suppressors of HbF production. lncRNAs, such as BGLT3 and NR_120526, exert diverse regulatory functions through chromatin remodeling, transcriptional regulation, and protein interactions. circRNAs, including hsa-circRNA-100466 and hsa-circRNA-0008102, exert an indirect effect on HbF, as they are thought to act as molecular sponges for miRNAs. The precise mechanism by which piRNAs contribute to HbF switching remains unclear; future studies should aim to map the complete regulatory networks of ncRNAs, elucidate their molecular interactions, and test therapeutic approaches in advanced preclinical and clinical settings for the treatment of β-hemoglobinopathies. Together, this review moves beyond the descriptive classification of ncRNA-mediated switching mechanisms toward an integrated regulatory model of HbF switching, and examines the therapeutic potential of targeting these networks to develop novel, next-generation treatment approaches for β-hemoglobinopathies.