Red Blood Cell Antioxidant State in Fanconi Anemia: The Highlighted Roles of Pi-Class Glutathione S-Transferase and Glutathione Peroxidase

Fanconi anemia (FA) is a rare bone marrow failure disorder characterized at the cellular level by hypersensitivity to alkylating agents, such as diepoxybutane (DEB), and redox imbalance. Alterations in red blood cells (RBCs), which play a key role in systemic antioxidant defense, are among the earliest changes in FA, consistent with an oxidative stress (OS) profile. Previous studies about antioxidant activity in RBCs from these patients are scarce and inconsistent. This study aimed to better understand the antioxidant profile in RBCs from FA patients carrying the homozygous <i>FANCA</i> c.295C>T variant. Glutathione content and the activities of catalase, superoxide dismutase, glutathione peroxidase (GPx), and Pi-class glutathione S-transferase (GSTP1) were quantified, both at baseline and after culture with and without DEB, in RBCs from FA patients, FA carriers, and controls. At baseline, FA RBCs displayed significantly reduced catalase activity, whereas GPx and GSTP1 activities were significantly increased, suggesting an OS preconditioning state, not observed in RBCs from FA carriers and controls. Under culture and DEB exposure, FA RBCs exhibited a significant decline in both GSTP1 and GPx activities, contrary to controls. These new findings highlight a key role of GSTP1 and GPx activities in baseline antioxidant defense, severely compromised in case of increased OS toxicity.