Inhibition of NLRP1 Inflammasome Activation by Tyrosine Kinase Inhibitors Restores Erythropoiesis in Diamond-Blackfan Anemia Syndrome
Diamond-Blackfan Anemia Syndrome (DBAS) is characterized by impaired erythropoiesis due to dysfunctional ribosome biogenesis and aberrant cellular signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome modulates erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis in Diamond-Blackfan anemia syndrome (DBAS) by inhibiting NLRP1 inflammasome activation. Specifically, nilotinib enhances erythroid differentiation in K562 cells through suppression of the ZAK/P38/NLRP1/CASP1 axis, leading to increased GATA1 protein levels and upregulation of key erythroid genes involved in iron acquisition, hemoglobin synthesis, and erythrocyte structure. These effects were validated in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, along with other TKIs (imatinib, dasatinib, and bosutinib), promoted erythropoiesis at the expense of myelopoiesis and reduced caspase-1 activity. Importantly, in RPS19-deficient zebrafish and human models and HSPCs from patients with DBAS, nilotinib, imatinib and dasatinib rescued defective erythroid differentiation and restored hemoglobin levels. These findings highlight the potential of TKIs to address the erythroid defects observed in ribosomopathies like DBAS. Given the limited treatment options available for DBAS and other congenital anemias, our study provides compelling evidence for repurposing TKIs as a novel therapeutic strategy to alleviate pathological NLRP1 activation and improve erythropoiesis. This work opens new avenues for managing ribosome-related disorders and advancing personalized medicine approaches for hematopoietic diseases.