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

ABSTRACT: 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-β (TGF-β) 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-β 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314453 | GEO | 2025/12/24

REPOSITORIES: GEO

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

Project description: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-β (TGF-β) 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-β 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.

2025-12-24 | GSE314452 | GEO

Ruxolitinib reduces macrophage pyroptosis in aplastic anaemia

Project description:Aplastic anaemia (AA) is a disease that shows complex pathogenesis involving multiple immune factors. While immunosuppressive therapies such as cyclosporine can effectively control AA, they may be ineffective in certain patients or those with relapse. Therefore, new treatments are needed. Among the targets for these treatments, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway regulates inflammatory cytokines and immune activation. Ruxolitinib, a JAK1/2 inhibitor, reduces T-cell activation and the associated inflammatory response and improves AA disease status in mice. However, its mechanism of action is unclear; thus, further research is needed before its clinical use. We previously showed increased pyroptosis in patients with severe AA (SAA) and that macrophage pyroptosis is an important factor in immune activation. The current study investigated the interaction of ruxolitinib with macrophages and whether the drug could treat SAA by improving pyroptosis levels. We induced differentiation of the THP-1 human monocyte cell line into macrophages in vitro and then induced pyroptosis. After constructing a macrophage pyroptosis model, treatment with different concentrations of ruxolitinib was administered. The results showed that ruxolitinib reduced the levels of pyroptosis and inflammatory-related factors. A mouse model of SAA was validated. In conclusion, ruxolitinib may treatment affects SAA by reducing the level of macrophage pyroptosis.

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