Does deteriorating oxidative defence and impaired γ-glutamyl cycle drive pathophysiology in individuals with sickle cell disease?

ickle cell disease (SCD) is a global health crisis, affecting two-thirds of the children born in Africa and India. Oxidative stress, pivotal in SCD pathophysiology, induces endothelial dysfunction and inflammation. This study reassesses oxidative stress in SCD via intricate interplay of metabolites, antioxidant enzymes, and ion profiles. We assessed the plasma elemental levels of SCD patients, trait and healthy controls (n=10) via ICP-MS. Additionally, comparative erythrocyte metabolomics of SCD and healthy (n=5) was carried out using LC-MS mass-spectrometry. Followed by assessment of antioxidant defence (AD) enzymes such as glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) in erythrocytes and plasma of SCD patients (n=31) compared to trait (n=8) and healthy (n=9). In principal component analysis, 442 metabolic features clustered separately with 135 exhibiting differential expression in the SCD vs HC. In SCD, upregulation of N6,N6,N6-Trimethyl-L-lysine, Pyroglutamate and 2-Aminoisobutyric while downregulation of Glutathione, Aminolevulinate and D-Glutamine was observed. SCD suffered dysregulations in D-Glutamine/Glutamate, Sphingolipid, Arginine biosynthesis, Gly/SerThr, β-Alanine, and Glutathione pathway. In SCD, plasma ion profiling yielded an elevated 24Mg, 44Ca, 66Zn,208Pb,39K and a decreased 57Fe,77Se, 85Rb indicating hemolysis, ion-channelopathy and anemia. SCD exhibited repressed activities of GR, SOD, and CAT in erythrocytes and plasma. SCD-RBCs displayed negligible GR and CAT activity changes, while trait and HC exhibited significant AD activity increase under hypoxia. Our findings highlight metabolic deregulations in SS-RBCs, a compromised antioxidant defence, reduced heme synthesis, ion-channel dysfunction, a shift to ATP consuming aberrant γ-glutamyl cycle leading to clinical manifestations such as oxidative stress, anemia, dehydration and hemolysis.