Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%–5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.

铁超载会导致进行性器官损伤，并与关节炎、肝损伤和心力衰竭有关。 1%–5% 的人铁水平升高；然而，铁超负荷的监测和诊断不足。影响铁稳态的遗传因素正在出现。遗传性干细胞增多症是一种罕见疾病，其机械敏感性 PIEZO1 离子通道出现功能获得性 (GOF) 突变，患有遗传性干细胞增多症的个体会出现随年龄增长而出现的铁超载。我们发现小鼠体内 GOF Piezo1等位基因的组成型或巨噬细胞表达会破坏铁调节剂铁调素的水平并导致铁过载。我们进一步表明 PIEZO1 是巨噬细胞吞噬活性和随后的红细胞周转的关键调节因子。引人注目的是，我们发现 E756del（一种温和的 GOF PIEZO1等位基因，存在于三分之一的非洲人后裔中）与血浆铁增加密切相关。我们的研究将巨噬细胞机械转导与铁代谢联系起来，并确定了非洲裔美国人铁水平升高的遗传风险因素。