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<p>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&#xa0;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.</p>

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TKI-mediated inhibition of NLRP1 inflammasome restores erythropoiesis in DBA syndrome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月9日

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  • Juan M Lozano-Gil,
  • Lola Rodríguez-Ruiz,
  • Manuel Palacios,
  • Jorge Peral,
  • Susana Navarro,
  • José L Fuster,
  • Cristina Beléndez,
  • Andrés Jérez,
  • Laura Murillo-Sanjuán,
  • Cristina Díaz-de-Heredia,
  • Guzmán López-de-Hontanar,
  • Josune Zubicaray,
  • Julián Sevilla,
  • Francisca Ferrer-Marín,
  • María P Sepulcre,
  • María L Cayuela,
  • Diana García-Moreno,
  • Alicia Martínez-López,
  • Sylwia D Tyrkalska,
  • Victoriano Mulero

摘要

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.