2026/01/09 by Juan M. Lozano-Gil, Lola Rodríguez-Ruiz, Manuel Palacios +17 · 1 voice
Biochemistry, Genetics and Molecular Biology · Energy · Medicine · #Metalloenzymes and iron-sulfur proteins #RNA modifications and cancer #Sirtuins and Resveratrol in Medicine
paper · pdf · doi:10.1038/s44321-025-00368-3
openalex created_date 2026/01/09 · openalex publication_date 2026/01/09 · openalex updated_date 2026/07/23
Diamond-Blackfan anemia syndrome (DBAS) is marked by defective erythropoiesis caused by impaired ribosome biogenesis and aberrant signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome affects erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis by inhibiting NLRP1 inflammasome activation. In K562 cells, nilotinib suppresses the ZAKα/P38/NLRP1/CASP1 axis, leading to increased GATA1 levels and upregulation of key erythroid genes. These effects were validated in human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, imatinib, and dasatinib promoted erythropoiesis while reducing caspase-1 activity. In Rps19-deficient zebrafish, RPS19-deficient human HSPCs, and HSPCs from DBAS patients, TKIs rescued erythroid differentiation and restored hemoglobin levels. Our findings highlight that targeting the NLRP1 inflammasome with TKIs may provide a novel therapeutic strategy for DBAS and other ribosomopathies.