Luspatercept with Immunosuppression Reducess Inflammation in Patients with Severe Aplastic Anemia by Inhibiting Monocyte Pyroptosis [RNA-Seq]

Aplastic anemia (AA) is a bone marrow failure disorder caused by diverse etiologies. AA pathogenesis involves aberrant immune activation and an imbalanced inflammatory bone marrow microenvironment. Previous studies have shown that inhibition of transforming growth factor-ß (TGF-ß) signaling in patients with AA can improve multilineage hematopoietic recovery and immune balance. This study is the first to demonstrate the synergistic mechanisms of TGF-ß inhibitor luspatercept in combination with Cyclosporine and Eltrombopag for the treatment of severe aplastic anemia (SAA) by acting on monocytes. The aim was to explore the effects of the drug Luspatercept on monocyte cell lines by performing RNA-seq after treating the THP-1 cell line. Mechanistic investigations further showed luspatercept suppressed pyroptosis in monocytes, reshaping the immune microenvironment, and attenuating pro-inflammatory cytokine secretion and cytotoxic molecule expression in CD8+T cells. This groundbreaking study uncovers that Luspatercept can reduce inflammation and pyroptosis through multi-target immune modulation, which provides a novel therapeutic strategy for AA. Overall design: We used the human mononuclear cell line THP-1 and induced pyroptosis with ATP and LPS. Based on whether Luspatercept was used in combination with cyclosporine and eltrombopag, three samples were divided into four groups: normal control (NC), pyroptosis model (PM, without drug intervention), pyroptosis model with cyclosporin A + eltrombopag (CE), and pyroptosis model with cyclosporin A + eltrombopag + luspatercept (CEL). RNA transcriptome sequencing was performed.