Ferroptosis Susceptibility in Pediatric Immune Thrombocytopenia: Alteration in Mesenchymal Stromal Cells.

Abstract

Immune thrombocytopenia (ITP) is the most common pediatric thrombocytopenia, characterized by immune-mediated platelet destruction and altered inflammatory responses. Among these alterations, mesenchymal stromal cells (MSCs) from ITP patients display reduced viability and impaired immunoregulatory functions. Our previous work revealed dysregulated iron metabolism in ITP-MSCs, with increased intracellular iron accumulation driven by hepcidin-FPN1 axis disruption and overexpression of iron importers. Given the link between iron overload, oxidative stress, and ferroptosis, a regulated iron-dependent form of cell death, we investigated whether ITP-MSCs exhibit oxidative and molecular alterations associated with ferroptosis. ITP-MSCs showed increased ROS levels and ACSL4 expression, together with reduced expression of proteins involved in ferroptosis-related antioxidant defense, including SLC3A2, SLC7A11, and GPX4. Increased extracellular release of HMGB1, a DAMP associated with cellular stress and different forms of regulated cell death, was also observed. Treatment with Ferrostatin-1 (Fer-1) and Deferasirox (DFX) reduced oxidative stress and partially restored the expression of ferroptosis-related markers. Similarly, high-dose dexamethasone (HD-Dexa) reduced ROS and ACSL4 levels and limited extracellular HMGB1 release. Collectively, these findings support increased susceptibility to ferroptotic stress in ITP-MSCs and reveal a ferroptosis-associated oxidative stress phenotype with concomitant alterations in ferroptosis-related molecular pathways. Moreover, the effects of HD-Dexa, DFX, and Fer-1 suggest that modulation of these pathways may represent a potential strategy for limiting oxidative cellular damage in ITP-MSCs.