Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms
Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms
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金诺芬通过不同的机制减轻全身铁过载并诱导铁死亡
DOI：
10.1038/s41392-020-00253-0
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发表时间：
2020-07-31
影响因子：
39.3
通讯作者：
Wang, Fudi
中科院分区：
文献类型：
--
作者：
Yang, Lei;Wang, Hao;Wang, Fudi
铁的体内平衡对健康至关重要；此外，hepcidin缺乏导致遗传性血色素沉着症和铁负荷性贫血的铁超载。在这里，我们通过使用640种fda批准的人肝Huh7细胞药物库对hepcidin激动剂进行功能性筛选，确定了铁调节剂。我们在C57BL/6J小鼠和血色素沉着症小鼠模型（Hfe - / -小鼠）中验证了结果。我们的筛选显示抗类风湿关节炎药物auranofin （AUR）能有效上调hepcidin的表达。有趣的是，我们发现调节铁的典型信号通路，包括Bmp/Smad和IL-6/Jak2/Stat3通路，在介导AUR的作用中起着不可或缺的作用。此外，AUR通过NF-κB途径诱导IL-6。在C57BL/6J小鼠中，急性给予5 mg/kg AUR可激活肝脏IL-6/hepcidin信号，降低血清铁和转铁蛋白饱和度。然而，长期给予雄性fe - / -小鼠5 mg/kg AUR可激活肝脏IL-6/hepcidin信号，减少全身铁超载，但对雌性效果较差。进一步的分析表明，雌激素降低了AUR诱导Huh7细胞中IL-6/hepcidin信号传导的能力，这为AUR在雌性hfe - / -小鼠中无效提供了机制解释。值得注意的是，高剂量AUR （25 mg/kg）通过抑制硫氧还蛋白还原酶（TXNRD）活性诱导铁下垂并引起脂质过氧化。我们证明了铁下垂抑制剂铁抑素显著保护高剂量AUR引起的肝毒性，而不包括其对铁代谢的有益作用。总之，我们的研究结果提供了令人信服的证据，证明TXNRD是铁下垂的关键调节因子，而AUR是hepcidin和铁下垂的一种新的激活剂，其机制不同，为治疗血色素沉着症和hepcidin缺乏症提供了一种有希望的方法。
Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe−/−mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR’s effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating maleHfe−/−mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in femaleHfe−/−mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.