Luspatercept with Immunosuppression Reducess Inflammation in Patients with Severe Aplastic Anemia by Inhibiting Monocyte Pyroptosis [scRNA-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. Single-cell RNA sequencing revealed increased inflammatory cytokine levels and elevated expression of pyroptosis-related genes in monocytes after luspatercept withdrawal. 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: Single-cell sequencing was performed on effective nodes and relapse nodes after discontinuation of Luspatercept in a 40-year-old female patient with SAA.