Metabolomic and Proteomic Profiling of Vaso-Occlusive Crises in Sickle Cell Disease: Current Evidence and Future Perspectives.

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crises (VOCs), which are the primary contributors to morbidity and mortality globally. Conventional clinical markers, including fetal hemoglobin (HbF), reticulocyte count, and lactate dehydrogenase (LDH), offer limited predictive value because of interpatient variability and an inability to capture the complex, multifactorial pathophysiology of VOCs. Recent advances in metabolomics and proteomics have enhanced understanding of VOC biology. Metabolomic profiling has identified perturbations in glycolysis, amino acid metabolism, oxidative stress pathways, and lipid metabolism, while proteomic studies have revealed dysregulation of inflammatory mediators, adhesion molecules, coagulation factors, and endothelial markers. Although significant progress has been made, most reported metabolomic and proteomic signatures remain insufficiently reproducible and are not yet clinically applicable. This limitation is primarily attributed to biological heterogeneity, limited cohort sizes, and methodological inconsistencies across studies. Recent evidence indicates that pathway-level markers, longitudinal sampling strategies, and integrated multi-omics approaches are more likely to yield clinically relevant biomarkers than isolated single-molecule candidates. Significant challenges remain, including limited validation across diverse populations and barriers to implementation in resource-limited settings. Addressing these challenges will require collaborative, multicenter studies, improved analytical harmonization, and the development of accessible diagnostic platforms. This narrative review synthesizes current evidence on metabolomic and proteomic profiling of VOCs, highlights implications for equity and global health, and outlines priorities for translational research to advance personalized care and improve clinical outcomes in SCD.