Transcriptomic signatures of hydroxyurea response in sickle cell disease

Abstract Background Hydroxyurea (HU) has been widely used as a first-line therapy for sickle cell disease (SCD), an autosomal recessive monogenic disorder characterized by abnormal haemoglobin and chronic haemolysis. However, its multiple mechanisms of action, particularly those related to SCD pathogenesis, remain incompletely understood. Methods We characterized the transcriptional profiles of erythroid cells differentiated from peripheral blood mononuclear cells collected from patients with SCD, either treated with HU or untreated, and compared them with healthy controls (HC) using bulk RNA sequencing. Results We identified 1398 differentially expressed genes (DEGs) in erythroid cells derived from untreated patients with SCD and 495 DEGs in cells derived from HU-treated patients, both compared with HC. Functional enrichment analysis using gene ontology and Kyoto encyclopedia of genes and genomes revealed significant enrichment of biological processes and pathways, including oxidative phosphorylation, proteasome function, autophagy, natural killer cell cytotoxicity, adaptive immune response, and inflammatory response. Additionally, 12 of the top DEGs identified in patients with SCD were validated by quantitative RT-PCR in comparison with HC. Conclusions The identified genes and pathways could play a role in SCD pathogenesis and may serve as potential targets for the development of novel therapeutic strategies.