Hypoxia, Inflammation, and Cytokine Crosstalk in Sickle Cell Disease: From Mechanisms to Modulation- A Narrative Review.

Sickle cell disease (SCD) is a genetically inherited group of hemoglobinopathies characterized by the polymerization of hemoglobin S, chronic hemolytic anemia, and vaso-occlusion. The interplay between inflammation and hypoxia is central to the pathophysiologic manifestations of SCD and drives many of its complications. In this narrative review, we explore the bidirectional relationship between inflammatory pathways and hypoxic stress, with a focus on immune dysregulation, endothelial activation, and redox imbalance. The paper also highlights how mitochondrial dysfunction, reactive oxygen species (ROS) generation, glycolytic shifts affecting 2,3-diphosphoglycerate (2,3-DPG), and complement activation contribute to disease exacerbation. The review critically examines limitations of in vitro and animal models in mimicking the complex human pathophysiology, underscoring the need for translational research and clinical studies, especially in low- and middle-income countries (LMICs). Additionally, the paper evaluates emerging therapeutic interventions targeting inflammatory and hypoxia-related pathways, including small molecules, biologics, and gene-modifying strategies. Recognizing the heterogeneity in disease severity, this narrative review emphasizes the importance of personalized treatment approaches, integration of non-invasive biomarkers, and enhanced infrastructure for clinical trials in resource-limited settings.