Inhibition of NLRP1 Inflammasome Activation by Tyrosine Kinase Inhibitors Restores Erythropoiesis in Diamond-Blackfan Anemia Syndrome

Diamond-Blackfan Anemia Syndrome (DBAS) is characterized by impaired erythropoiesis due to dysfunctional ribosome biogenesis and aberrant cellular signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome modulates erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis in Diamond-Blackfan anemia syndrome (DBAS) by inhibiting NLRP1 inflammasome activation. Specifically, nilotinib enhances erythroid differentiation in K562 cells through suppression of the ZAKa/P38/NLRP1/CASP1 axis, leading to increased GATA1 protein levels and upregulation of key erythroid genes involved in iron acquisition, hemoglobin synthesis, and erythrocyte structure. These effects were validated in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, along with other TKIs (imatinib, dasatinib, and bosutinib), promoted erythropoiesis at the expense of myelopoiesis and reduced caspase-1 activity. Importantly, in RPS19-deficient zebrafish and human models and HSPCs from patients with DBAS, nilotinib, imatinib and dasatinib rescued defective erythroid differentiation and restored hemoglobin levels. These findings highlight the potential of TKIs to address the erythroid defects observed in ribosomopathies like DBAS. Given the limited treatment options available for DBAS and other congenital anemias, our study provides compelling evidence for repurposing TKIs as a novel therapeutic strategy to alleviate pathological NLRP1 activation and improve erythropoiesis. This work opens new avenues for managing ribosome-related disorders and advancing personalized medicine approaches for hematopoietic diseases. Overall design: K562 cells were pretreated with 0.1 µM nilotinib, followed by differentiation with 50 µM hemin for 24 h. Three biological replicates (15 µl at 200 ng/µl)

戴蒙德-布莱克范贫血综合征（Diamond-Blackfan Anemia Syndrome, DBAS）以核糖体生物发生功能异常、细胞信号通路紊乱所致的红细胞生成障碍为典型特征。本研究探讨了核糖体应激诱导的NLRP1炎性小体（NLRP1 inflammasome）活化如何调控戴蒙德-布莱克范贫血综合征的红细胞分化进程。研究证实，美国食品药品监督管理局（FDA）与欧洲药品管理局（EMA）批准的酪氨酸激酶抑制剂（Tyrosine Kinase Inhibitors, TKIs）可通过抑制NLRP1炎性小体活化，有效改善戴蒙德-布莱克范贫血综合征的红细胞生成缺陷。
具体而言，尼洛替尼（nilotinib）可通过抑制ZAKα/P38/NLRP1/CASP1信号轴，增强K562细胞的红细胞分化能力，提升GATA1蛋白表达水平，并上调铁摄取、血红蛋白合成及红细胞结构相关的关键红细胞系基因的表达。上述效应在人类CD34阳性造血干细胞与祖细胞（CD34+ hematopoietic stem and progenitor cells, HSPCs）及斑马鱼模型中得到验证：尼洛替尼与其他酪氨酸激酶抑制剂（伊马替尼imatinib、达沙替尼dasatinib及博舒替尼bosutinib）均可促进红细胞生成，同时抑制髓系生成，并降低半胱天冬酶-1（caspase-1）的活性。
尤为重要的是，在RPS19缺陷型斑马鱼、人类模型以及戴蒙德-布莱克范贫血综合征患者的造血干细胞与祖细胞中，尼洛替尼、伊马替尼与达沙替尼可挽救红细胞分化缺陷，恢复血红蛋白水平。本研究结果凸显了酪氨酸激酶抑制剂用于改善核糖体病（如戴蒙德-布莱克范贫血综合征）相关红细胞生成缺陷的潜在价值。鉴于戴蒙德-布莱克范贫血综合征及其他先天性贫血的治疗选择极为有限，本研究提供了有力证据，支持将酪氨酸激酶抑制剂作为全新治疗策略进行药物重定位，以缓解病理性NLRP1活化并改善红细胞生成。本研究为核糖体相关疾病的临床管理以及造血系统疾病的个性化医疗方案开发开辟了全新方向。
实验整体设计：将K562细胞以0.1 μmol/L浓度的尼洛替尼预处理，随后以50 μmol/L浓度的血红素诱导分化24小时。设置3次生物学重复（样本浓度为200 ng/μL，体积15 μL）。