Hereditary hemochromatosis (HH) is one of the most common genetic disorders in Caucasian populations, with no viable therapeutic options except phlebotomy. We describe a zebrafish model of human HH (HH) created by targeted mutagenesis of the gene encoding transferrin receptor 2 (tfr2). TFR2 mutations in humans lead to HH Type 3, a rare but severe form of the disease. The tfr2 mutant model in zebrafish recapitulates the defining features of HH3: iron overload and suppression of hepcidin, the iron regulatory hormone. Using in vivo chemical screens in zebrafish embryos, we identify a new small molecule inducer of hepcidin: SC-514, a specific chemical inhibitor of NFkB signaling. Using independent small molecule inhibitors of the NFkB pathway, we demonstrate that inhibition of NFkB signaling causes induction of hepcidin transcription and reduction of iron overload in the HH3 model. This first successful chemical intervention for hereditary hemochromatosis may also have relevance in treatment of other very prevalent iron regulatory iron overload disorders such as thalassemia.

中文翻译：

---

NFkB的小分子抑制剂可逆铁过载和铁调素在斑马鱼模型中的遗传性3型血色素沉着模型中。

遗传性血色素沉着病（HH）是高加索人群中最常见的遗传性疾病之一，除了放血术外没有其他可行的治疗选择。我们描述了由编码转铁蛋白受体2（tfr2）的基因的定向诱变创建的人类HH（HH）的斑马鱼模型。人类的TFR2突变会导致3型HH，这是一种罕见但严重的疾病。该TFR2斑马鱼的突变模型概括了HH3的主要特征：铁过载和铁调节激素hepcidin的抑制。使用斑马鱼胚胎中的体内化学筛选，我们确定了铁调素的一种新的小分子诱导剂：SC-514，一种特定的NFkB信号化学抑制剂。使用独立的小分子抑制剂的NFkB途径，我们证明了NFkB信号的抑制会导致hepcidin转录的诱导和HH3模型中铁超载的减少。这是遗传性血色素沉着症的第一个成功的化学干预措施，也可能与其他非常普遍的铁调节铁超负荷疾病（如地中海贫血）的治疗有关。