Eltrombopag restores T-cell homeostasis in aplastic anemia by regulating oxidative metabolism and reactive oxygen species levels

Aplasticanemia (AA) is an autoimmune-mediated bone marrow failure syndrome characterized by excessive T-cell activation and destruction of hematopoietic stem and progenitor cells. Eltrombopag (ELT), a Thrombopoietin Receptor Agonist, has been shown to promote hematopoiesis and exert immunomodulatory effects. However, its role in regulating T cells in AA remains unclear. This study aimed to investigate whether ELT modulates the T-cell functional phenotype via the oxidative metabolism pathway. Using single-cell RNA Sequencing of AA mouse models under different treatment regimens, we identified differentially expressed genes in T-cell subsets associated with oxidative stress. ELT treatment effectively reduced Reactive Oxygen Species (ROS) levels in both CD4⁺ and CD8⁺ T cells, reshaped T-cell subset composition, and attenuated cytotoxic activity. Mechanistically, Western blot analysis confirmed that ELT significantly upregulated ENPP1 and ENTPD5, which are involved in oxidative metabolism. Collectively, these findings reveal a previously unrecognized mechanism through which ELT restores T-cell homeostasis by fine-tuning oxidative metabolism, highlighting its therapeutic potential beyond hematopoietic stimulation in AA.