Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms  

作　　者：Lei Yang Hao Wang Xiang Yang Qian Wu Peng An Xi Jin Weiwei Liu Xin Huang Yuzhu Li Shiyu Yan Shuying Shen Tingbo Liang Junxia Min Fudi Wang 

机构地区：[1]Department of Nutrition,Precision Nutrition Innovation Center,School of Public Health,Zhengzhou University,450001 Zhengzhou,China [2]The First Affiliated Hospital,School of Public Health,Institute of Translational Medicine,Zhejiang University School of Medicine,310058 Hangzhou,China [3]Department of Nutrition and Health,Beijing Advanced Innovation Center for Food Nutrition and Human Health,China Agricultural University,100193 Beijing,China [4]School of Nursing,Xinxiang Medical University,453003 Xinxiang,China

出　　处：《Signal Transduction and Targeted Therapy》2020年第1期1239-1247,共9页信号转导与靶向治疗（英文）

基　　金：supported by research grants from the National Natural Science Foundation of China(31530034 and 31930057 to F.W.,31570791 to J.M.,31701035 to H.W.,31701034 to Q.W.,and 81500984 to L.Y.);the National Key Research and Development Program of China(2018YFA0507802 to F.W.,2018YFA0507801 to J.M.).

摘　　要：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 male Hfe^(−/−)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 female Hfe^(−/−)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 highdose 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.

关 键 词：PEROXIDATION OVERLOAD MECHANISMS 

分 类 号：R556.3[医药卫生—血液循环系统疾病]