Therapeutic Silencing of Tmprss6 Reduces Iron-Induced Inflammation and Prolongs Survival in MDS Mice

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Despite advances in supportive and targeted therapies, disease-modifying interventions remain limited. Iron overload is increasingly recognized as a key driver of disease progression, amplifying oxidative stress and inflammation while impairing hematopoietic function. However, the mechanisms by which sustained iron excess contributes to disease evolution remain poorly understood. Hepcidin, the master regulator of systemic iron homeostasis, is produced by hepatocytes in response to iron and inflammatory cues and is negatively regulated by transmembrane protease serine 6 (TMPRSS6). Targeting TMPRSS6 to increase endogenous hepcidin offers a promising strategy to restrict iron overload and its inflammatory consequences. Here, we investigated hepatocyte-targeted silencing of Tmprss6 using a GalNAc-conjugated siRNA (SLN124) in the NUP98-HOXD13 (NHD13) mouse model of MDS. MDS and wild-type mice received monthly subcutaneous SLN124 (3 mg/kg) or oral deferiprone (1.25 mg/mL). Iron burden in MDS mice strongly correlated with ASC-speck formation in CD45⁺ hematopoietic cells, consistent with inflammasome activation. Both SLN124 and deferiprone reduced tissue iron deposition and ASC-speck abundance, with SLN124 producing the most pronounced effect. Long-term SLN124 treatment delayed disease progression and significantly prolonged survival, with 30% of treated mice surviving beyond 450 days compared with complete mortality by Day 420 in controls and deferiprone-treated mice. These findings demonstrate that Tmprss6 inhibition via SLN124 suppresses iron-driven inflammation, and mitigated disease progression in MDS mice, establishing TMPRSS6 silencing as a promising disease-modifying therapeutic approach.