title: Characterization of ferroptosis in murine models of hemochromatosis.
abstract: Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow-derived macrophages. Next, we screened for ferroptosis in mice fed a high-iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high-iron diet and in two knockout mouse lines that develop severe iron overload (Hjv-/-and Smad4Alb/Albmice) but not in a third line that develops only mild iron overload (Hfe-/-mice). Moreover, we found that iron overload-induced liver damage was rescued by the ferroptosis inhibitor ferrostatin-1. To identify the genes involved in iron-induced ferroptosis, we performed microarray analyses of iron-treated bone marrow-derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis-related gene, was significantly up-regulated in iron-treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron-treated hepatocytes and bone marrow-derived macrophages isolated from Slc7a11-/-mice fed a high-iron diet.
  
  
  
  We found that iron treatment induced ferroptosis in Slc7a11-/-cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high-iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11-mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis-related tissue damage. (Hepatology 2017;66:449-465).
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: An
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Enjun
authors.initials: E
authors.lastname: Xie
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xuexian
authors.initials: X
authors.lastname: Fang
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhuzhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Guoli
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Min
authors.affiliation: School of Public Health, Zhengzhou University; School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000494:pharmacology*; D006432:Hemochromatosis / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D005290:Ferric Compounds; D007502:Iron Chelating Agents; C491209:Mchr1 protein, mouse; D017481:Receptors, Somatostatin; C025314:ferric citrate; D007501:Iron