Impact of iron chelation therapy on mitochondrial function, vascular integrity and inflammation in transfusion-dependent Myelodysplastic Syndromes

Regina García-Delgado^1,2,3Gloria Moreno-Carrasco¹Manuel Carrasco-Gomariz⁴Silvia García-Segovia^1,2Rodolfo Matias Ortiz-Flores^2*Julio Torres-González²Gonzalo Gallego-Fuillerat³Juan Antonio López-Villodres³Alejandro Escamilla-Sanchez^2,3*

• ¹Hospital Universitario Virgen de la Victoria, UGC Hematología y Hemoterapia, Málaga, Spain
• ²IBIMA Plataforma BIONAND, BE21-Hematología e Inmunoterapia, Málaga, Spain
• ³Universidad de Málaga, Facultad de Medicina, Departamento de Fisiología Humana, Histología Humana, Anatomía Patológica y Educación Físico-Deportiva, Málaga, Spain
• ⁴Hospital Universitario Virgen de la Victoria, UGC Farmacia, Málaga, Spain

Background: Patients with myelodysplastic syndromes (MDS) frequently develop chronic transfusion dependence, leading to progressive iron overload. This accumulation of non-transferrin-bound iron (NTBI) contributes to oxidative stress, mitochondrial dysfunction, endothelial damage, impaired vascular regeneration, and heightened inflammation. Objectives: To assess whether iron chelation therapy can reverse cellular and vascular injury, redox imbalance, and immune dysfunction in transfusion-dependent MDS patients. Methods: Peripheral blood from 23 transfusion-dependent MDS patients was analysed in a paired pre-/post-treatment design. Patients received daily oral deferasirox at standard clinical dosing for approximately 6 months (median). Flow cytometry was employed to evaluate reactive oxygen species (ROS), expression of adhesion molecules, mitochondrial membrane potential, circulating endothelial progenitor cells (EPCs), and intracellular levels of key pro-inflammatory cytokines. Results: Chelation therapy was associated with a ~55% decrease in serum ferritin and robust redox recovery: leukocyte H₂O₂ and superoxide decreased ~3.8-fold and ~3.2-fold, respectively (both p<0.0001), intracellular glutathione increased ~3.3-fold (p<0.0001), and mitochondrial membrane potential rose ~2.6-fold (p<0.0001). Endothelial injury and adhesion were attenuated (Annexin V ~2-fold↓; ICAM-1 ~33%↓; VCAM-1 ~15%↓; E-selectin ~25%↓; P-selectin ~52%↓; all p<0.0001), while endothelial progenitors and mature endothelial cells increased ~2.4–2.5-fold (both p<0.0001). Pro-inflammatory cytokines IL-1 (p=0.0013), IL-3, IL-6 and TNF-α (all p<0.0001) decreased, whereas IFN-γ increased (p<0.0001) consistent with attenuation of NF-κB-related inflammatory signalling and partial immune reactivation. Conclusions: Iron chelation may modulate disease-relevant redox, endothelial, and cytokine pathways in transfusion-dependent MDS, generating mechanistic hypotheses for prospective clinical validation. These findings support the concept that NTBI reduction mitigates pathogenic processes relevant to disease progression, warranting confirmation in prospective studies integrating clinical endpoints