TKI-mediated inhibition of NLRP1 inflammasome restores erythropoiesis in DBA syndrome
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.
Authors
- Jorge Peral
- M.A. Palacios (ORCID: https://orcid.org/0000-0001-6750-384X)
- Josune Zubicaray (ORCID: https://orcid.org/0000-0003-4115-9598)
- Sylwia D. Tyrkalska (ORCID: https://orcid.org/0000-0001-6654-0163)
- María P. Sepulcre (ORCID: https://orcid.org/0000-0001-6213-2744)
- Guzman Lopez-de-Ontanar
- Juan M. Lozano-Gil
- Cristina Beléndez
- Victoriano Mulero
- Laura Murillo-Sanjuán
- Cristina Díaz-de-Heredia
- Julián Sevilla
- Andrés Jérez
- Diana García-Moreno
- José L Fuster
- Lola Rodríguez-Ruiz
- María L Cayuela
- Susana Navarro
- Alicia Martínez-López
Institutions
- Hospital General Universitario Gregorio Marañón (ES)
- Hospital General Universitario Morales Meseguer (ES)
- Hospital Infantil Universitario Niño Jesús (ES)
- Centro de Investigación Biomédica en Red (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Hospital Universitario Virgen de la Arrixaca (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Universidad Autónoma de Madrid (ES)
- Universidad de Murcia (ES)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-01-09
- DOI
- https://doi.org/10.1038/s44321-025-00368-3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00