Role of FOXO3 in regulation of redox homeostasis and promotion of red blood cell longevity in sickle cell disease

초록

Sickle cell disease (SCD) is a severe monogenic red blood cell (RBC) disorder that follows a simple Mendelian mode of inheritance. SCD is characterized by hemoglobin S polymerization under deoxygenated conditions, leading to chronic hemolysis and vaso-occlusive complications. Increasing evidence indicates that oxidative stress plays a central pathogenic role in SCD complications. Forkhead box O3 (FOXO3) is a key transcription factor involved in different cellular mechanisms, including apoptosis, autophagy, and cytoprotective signaling cascades. FOXO3, through its transcriptional modulation of enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, reduces reactive oxygen species burden, delays hemolysis, and contributes to RBC longevity. Beyond its antioxidant defense properties, FOXO3 interacts with other key molecular pathways, such as nuclear factor erythroid 2-related factor 2, nuclear factor kappa B, AMP-activated protein kinase, and sirtuin 1, which modulate vascular inflammation, nitric oxide bioavailability, and systemic redox homeostasis. Thus, by promoting antioxidant defense and facilitating autophagy, FOXO3 emerges as both a biomarker and a promising therapeutic target in SCD. This review provides key findings from the existing literature and precisely explores FOXO3's role in cellular stress responses, antioxidant defense, fetal hemoglobin production, erythropoiesis, and RBC longevity, as well as their implications for disease severity and therapeutic strategies in SCD. Future studies focusing on patient-specific FOXO3 activity by precision modulation and multi-omics sequencing will be essential to fully harness FOXO3's potential to achieve beneficial outcomes for individuals with SCD.

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