PUBLICATION
TKI-mediated inhibition of NLRP1 inflammasome restores erythropoiesis in DBA syndrome
- Authors
- Lozano-Gil, J.M., Rodríguez-Ruiz, L., Palacios, M., Peral, J., Navarro, S., Fuster, J.L., Beléndez, C., Jérez, A., Murillo-Sanjuán, L., Díaz-de-Heredia, C., López-de-Hontanar, G., Zubicaray, J., Sevilla, J., Ferrer-Marín, F., Sepulcre, M.P., Cayuela, M.L., García-Moreno, D., Martínez-López, A., Tyrkalska, S.D., Mulero, V.
- ID
- ZDB-PUB-260110-14
- Date
- 2026
- Source
- EMBO Molecular Medicine : (Journal)
- Registered Authors
- Mulero, Victor
- Keywords
- Diamond-Blackfan Anemia Syndrome, Drug Repurposing, NLRP1, Tyrosine Kinase Inhibitors, Zebrafish
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing*/antagonists & inhibitors
- Adaptor Proteins, Signal Transducing*/metabolism
- Anemia, Diamond-Blackfan*/drug therapy
- Anemia, Diamond-Blackfan*/pathology
- Animals
- Apoptosis Regulatory Proteins*/antagonists & inhibitors
- Apoptosis Regulatory Proteins*/metabolism
- Caspase 1/metabolism
- Disease Models, Animal
- Erythropoiesis*/drug effects
- GATA1 Transcription Factor/metabolism
- Hematopoietic Stem Cells/drug effects
- Humans
- Inflammasomes*/antagonists & inhibitors
- Inflammasomes*/metabolism
- K562 Cells
- NLR Proteins
- Protein Kinase Inhibitors*/pharmacology
- Pyrimidines/pharmacology
- Ribosomal Proteins/deficiency
- Ribosomal Proteins/genetics
- Zebrafish
- PubMed
- 41514124 Full text @ EMBO Mol. Med.
Citation
Lozano-Gil, J.M., Rodríguez-Ruiz, L., Palacios, M., Peral, J., Navarro, S., Fuster, J.L., Beléndez, C., Jérez, A., Murillo-Sanjuán, L., Díaz-de-Heredia, C., López-de-Hontanar, G., Zubicaray, J., Sevilla, J., Ferrer-Marín, F., Sepulcre, M.P., Cayuela, M.L., García-Moreno, D., Martínez-López, A., Tyrkalska, S.D., Mulero, V. (2026) TKI-mediated inhibition of NLRP1 inflammasome restores erythropoiesis in DBA syndrome. EMBO Molecular Medicine. :.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping