Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc
Journal website https://jh.elmerpub.com

Review

Volume 15, Number 5, October 2026, pages 225-235

Ferroptosis and Oxidative Stress in Sickle Cell Anemia

Figures

↓  Figure 1. Segment of the β chain of hemoglobin. It shows how the residue at position six is replaced by valine (HbS) and the chain with the aspartic acid residue hemoglobin A (HbA). HbS: hemoglobin S.
Figure 1.
↓  Figure 2. Mechanism of ferroptosis-mediated cell death during hemolysis and ischemia–reperfusion injury in SCD. SCD involves the accumulation of iron-induced lipid peroxides and an increase in ROS, leading to ferroptosis. Excessive hemolysis saturates the capacity of hemopexin, which elevates labile iron through HMOX1 and promotes lipid peroxidation through Fenton reactions. During ischemia–reperfusion, the restoration of blood flow generates an oxidative burst that increases lipid oxidation. In addition, uncoupled nitric oxide synthase, cytochrome P450, and lipoxygenase contribute to the formation of hydroxyl radicals, exacerbating damage to cell membranes. This process culminates in ferroptosis, a form of iron-dependent cell death that compromises membrane integrity and exacerbates tissue damage in SCD. ROS: reactive oxygen species; SCD: sickle cell disease; HMOX1: heme oxygenase 1.
Figure 2.

Table

↓  Table 1. Selected Studies for Screening for SCA and Its Associated Complications
 
StudyCountryAge range (year)DiagnosticComplicationsKey findingsReference
Hb: hemoglobin; HbA1c: glycated hemoglobin; HbF: fetal hemoglobin; CKD: chronic kidney disease; ROS: reactive oxygen species; SCA: sickle cell anemia; SCD: sickle cell disease.
1Ghana3–6SCAVascular occlusive crisis, chronic painElevated HbF levels in outpatients, greater resistance to erythrocyte sickling.Olupot-Olupot et al, 2023 [14]
2Sub-Saharan7–12SCAMalaria, hemolytic crisesHydroxyurea decreases the incidence of malaria and reduces vaso-occlusive crises.Lee et al, 2018 [15]
3Tanzania3–18Severe anemiaFerroptosis, frequent hemolysisLow levels of hepcidin associated with higher reticulocytes and free iron.Ximbi et al, 2024 [16]
4Tanzania> 18SCD with excess ironHbA1c due to the impact of ironInverse relationship between iron and HbA1c, especially in men. High iron levels reduce the reliability of HbA1c as a glucose markerKweka et al, 2019 [17]
5Kenia5–16SCD with severe anemia (Hb < 7 g/dL)CKD, persistent hypoxia, glomerular injuryOxidative stress and ferroptosis aggravate kidney damage. Controlling Hb levels is crucial to prevent CKD progression.Amarapurkar et al, 2022 [18]
6Democratic Republic of the Congo> 5SCD with mutation Q248HIncrease in ROS and lipid peroxidation in oxidative stressMutation reduces intracellular iron but facilitates its continuous export, increasing labile iron and complications from ferroptosis in SCD.Hailu, 2023 [19]
7Ethiopia, Tanzania, Mozambique> 5Mild and moderate anemiaInfections, vulnerability to disease, delayed growth and cognitive developmentHigh prevalence in rural areas due to malaria and iron deficiency.Aygun et al, 2020 [20]
8Sub-Saharan1–10SCAThrombocytopenia, anemia related to infections, malaria, neutropeniaSustained increases in hemoglobin (from 7.3 g/dL to 8.4 g/dL) and HbF (from 11% to 23–25%).Tshilolo et al, 2019 [21]
9Sub-Saharan1–10SCAPalpable splenomegaly, significant splenomegaly associated with low hemoglobin and platelet counts (hypersplenism), increased risk of malaria infectionsHydroxyurea improves HbF, but in children with splenomegaly it causes greater toxicity.Vargas-Hernandez et al, 2023 [22]
10Colombia5–38SCASCA (HbSS) and HbS/βthalassemia with clinical complicationsHbS and thalassemia are more prevalent. Sickle cell trait is the most common variant. No cases of hemoglobin CC (HbCC) were foundSoto et al, 2023 [23]