MOLECULAR CROSSTALK BETWEEN HYPOXIA INDUCIBLE FACTORS AND SICKLE CELL PATHOGENESIS: A NARRATIVE REVIEW

Abstract

Sickle cell disease (SCD) is a hereditary hemoglobin disorder marked by the polymerization of deoxygenated sickle hemoglobin (HbS), causing vaso-occlusion, hemolysis, and persistent inflammation, leading to substantial morbidity and mortality. Recent studies have found hypoxia-inducible factors (HIFs) to be crucial regulators in cellular reactions to low oxygen conditions, commonly seen in different tissues impacted by SCD. The activation of HIFs is essential in regulating erythropoiesis, vascular stability, and inflammation, which are all key to the pathophysiology of SCD. This review examines the molecular interactions between HIFs and essential disease processes, emphasizing their role in the intricate clinical presentations of SCD. HIFs, especially HIF-1, control various genes that play a role in erythropoiesis and the vascular reaction to low oxygen levels. In SCD, the rise in tissue hypoxia worsens erythropoietic dysregulation and leads to the atypical generation of sickled red blood cells, which are susceptible to early hemolysis. Moreover, HIFs stimulate inflammatory pathways by increasing the production of cytokines and adhesion molecules, resulting in endothelial dysfunction and microvascular blockages. The resulting inflammatory reaction drives a harmful cycle of blood vessel harm and organ injury, which is characteristic of complications in SCD. Peer Review History: Received 22 December 2025; Reviewed 9 January 2026; Accepted 17 February; Available online 15 March 2026 Academic Editor: Dr. Essam Mohamed Eissa, Beni-Suef University, Egypt, dressamceutics@yahoo.com Reviewers: Dr. Essam Mohamed Eissa, Beni-Suef – 32 Tahrir St, Egypt, dressamceutics@yahoo.com Dr. Julie Ann S. Ng, Blk 18 Lot 6 Grandville 3 Subdivision Mansilingan, Bacolod City, Philippines. julieann_ng@yahoo.com