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

## TL;DR

This study shows that repurposed tyrosine kinase inhibitors can restore red blood cell production in Diamond-Blackfan anemia by blocking a specific inflammatory pathway.

## Contribution

The paper introduces a novel therapeutic strategy for DBAS by repurposing FDA-approved TKIs to inhibit the NLRP1 inflammasome.

## Key findings

- TKIs like nilotinib, imatinib, and dasatinib promote erythropoiesis in zebrafish and human cells by inhibiting the ZAKα/NLRP1/CASP1 axis.
- Inhibition of the NLRP1 inflammasome stabilizes GATA1 and enhances erythroid differentiation in human HSPCs for up to 13 days.
- Findings support the repurposing of TKIs as a potential treatment for DBAS and related ribosomopathies.

## 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.

Repurposed tyrosine kinase inhibitors (TKIs) restore erythropoiesis in Diamond-Blackfan anemia syndrome (DBAS) by blocking the ZAKα/NLRP1 inflammasome-GATA1 pathway across zebrafish, CRISPR-edited human HSPCs, and patient cells, supporting rapid clinical translation.

Selected TKIs (nilotinib, dasatinib, imatinib) were shown to rescue erythropoiesis in RPS19-deficient zebrafish, RPS19-deficient human HSPCs, and DBAS patient-derived cells.Inhibition of the ZAKα/NLRP1/CASP1 axis was shown to stabilize GATA1 and promote erythroid differentiation of human HSPCs for up to 13 days in culture.Findings provide strong preclinical evidence supporting the repurposing of selected TKIs as a therapeutic strategy for DBAS and related ribosomopathies.

Selected TKIs (nilotinib, dasatinib, imatinib) were shown to rescue erythropoiesis in RPS19-deficient zebrafish, RPS19-deficient human HSPCs, and DBAS patient-derived cells.

Inhibition of the ZAKα/NLRP1/CASP1 axis was shown to stabilize GATA1 and promote erythroid differentiation of human HSPCs for up to 13 days in culture.

Findings provide strong preclinical evidence supporting the repurposing of selected TKIs as a therapeutic strategy for DBAS and related ribosomopathies.

Repurposed tyrosine kinase inhibitors (TKIs) restore erythropoiesis in Diamond-Blackfan anemia syndrome (DBAS) by blocking the ZAKα/NLRP1 inflammasome-GATA1 pathway across zebrafish, CRISPR-edited human HSPCs, and patient cells, supporting rapid clinical translation.