药学学报, 2017, 52(12): 1783-1790
俞鸿敏, 王敏, 毛中伏, 韩方璇, 李怡芳, 栗原博, 何蓉蓉. 新型细胞死亡方式ferroptosis在肝疾病机制中的研究前景[J]. 药学学报, 2017, 52(12): 1783-1790.
YU Hong-min, WANG Min, MAO Zhong-fu, HAN Fang-xuan, LI Yi-fang, KURIHARA Hiroshi, HE Rong-rong. The prospects of ferroptosis in the pathogenesis of liver disease[J]. Acta Pharmaceutica Sinica, 2017, 52(12): 1783-1790.

俞鸿敏1, 王敏2, 毛中伏1, 韩方璇2, 李怡芳1, 栗原博1, 何蓉蓉1
1. 暨南大学, 广东省中药药效物质基础和创新药物研究重点实验室, 广东 广州 510632;
2. 海南省人民医院药学部, 海南 海口 570311
关键词:    铁凋亡      活性氧      脂质过氧化作用      肝疾病     
The prospects of ferroptosis in the pathogenesis of liver disease
YU Hong-min1, WANG Min2, MAO Zhong-fu1, HAN Fang-xuan2, LI Yi-fang1, KURIHARA Hiroshi1, HE Rong-rong1
1. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China;
2. Department of Pharmacy, Hainan General Hospital, Haikou 570311, China
Ferroptosis is a novel type of cell death which induced by iron-dependent lipid peroxidation accumulation. This type of cell death is significantly different from other cell death in terms of morphology, genetics and biochemistry. It has been reported that ferroptosis is involved in a variety of human diseases, particularly in liver diseases. Therefore, screening and studying of inhibitors or activators of ferroptosis may provide novel strategies for prevention and treatment of liver diseases. This review provides the biological characteristics and regulatory signaling pathways of ferroptosis, as well as the relationship between ferroptosis and liver diseases, which will contribute to new insight into the pathogenesis of liver diseases.
Key words:    ferroptosis    reactive oxygen species    lipid peroxidation    liver diseases   
收稿日期: 2017-07-07
DOI: 10.16438/j.0513-4870.2017-0336
基金项目: 国家自然科学基金资助项目(81622050);海南省中药现代化专项资助项目(2015ZY01).
通讯作者: 何蓉蓉,Tel:86-20-85227791,E-mail:rongronghe@jnu.edu.cn
Email: rongronghe@jnu.edu.cn
PDF(290KB) Free
俞鸿敏  在本刊中的所有文章
王敏  在本刊中的所有文章
毛中伏  在本刊中的所有文章
韩方璇  在本刊中的所有文章
李怡芳  在本刊中的所有文章
栗原博  在本刊中的所有文章
何蓉蓉  在本刊中的所有文章

[1] Bergsbaken T, Fink SL, Cookson BT. Pyroptosis:host cell death and inflammation[J]. Nat Rev Microbiol, 2009, 7:99-109.
[2] Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death[J]. Curr Opin Cell Biol, 2010, 22:263-268.
[3] Wang Y, Dawson VL, Dawson TM. Poly(ADP-ribose) signals to mitochondrial AIF:a key event in parthanatos[J]. Exp Neurol, 2009, 218:193-202.
[4] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149:1060-1072.
[5] Angeli JPF, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator GPX4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16:1180-1191.
[6] Dolma S, Lessnick SL, Hahn WC, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3:285-296.
[7] Wan SY, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15:234-245.
[8] Xie Y, Hou W, Song X, et al. Ferroptosis:process and function[J]. Cell Death Differ, 2016, 23:369-379.
[9] Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death[J]. Nat Chem Biol, 2014, 10:9-17.
[10] Bröer S, Wagner CA. Structure-function relationships of heterodimeric amino acid transporters[J]. Cell Biochem Biophys, 2002, 36:155-168.
[11] Yang WS, Sriramaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156:317-331.
[12] Yang WS, Stockwell BR. Ferroptosis:death by lipid peroxidation[J]. Trends Cell Biol, 2016, 26:165-176.
[13] Hayano M, Yang WS, Corn CK, et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation[J]. Cell Death Differ, 2016, 23:270-278.
[14] Conrad M, Angeli JPF. Glutathione peroxidase 4(GPX4) and ferroptosis:what's so special about it?[J]. Mol Cell Oncol, 2015, 2:e995047.
[15] Imai H, Hirao F, Sakamoto T, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene[J]. Biochem Biophys Res Commun, 2003, 305:278-286.
[16] Chen L, Hambright WS, Na R, et al. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis[J]. J Biol Chem, 2015, 290:28097-28106.
[17] Mai M, Freigang S, Schneider C, et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection[J]. J Exp Med, 2015, 212:51-57.
[18] Tansey TR, Shechter I. Structure and regulation of mammalian squalene synthase[J]. Biochim Biophys Acta, 2000, 1529:49-62.
[19] Zhao X, Wang Y, Wang G, et al. Disruption of iron homeostasis and relevant pharmacotherapies in Alzheimer's disease[J]. Acta Pharm Sin (药学学报), 2016, 51:866-872.
[20] Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation[J]. Blood, 2003, 102:783-788.
[21] Magtanong L, Ko PJ, Dixon SJ. Emerging roles for lipids in non-apoptotic cell death[J]. Cell Death Differ, 2016, 23:1099-1109.
[22] Dixon SJ, Winter GE, Musavi LS, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death[J]. ACS Chem Biol, 2015, 10:1604-1609.
[23] Haeggström JZ, Funk CD. Lipoxygenase and leukotriene pathways:biochemistry, biology, and roles in disease[J]. Chem Rev, 2011, 111:5866-5898.
[24] Liu Y, Wang W, Li Y, et al. The 5-lipoxygenase inhibitor zileuton confers neuroprotection against glutamate oxidative damage by inhibiting ferroptosis[J]. Biol Pharm Bull, 2015, 38:1234-1239.
[25] Chen XS, Funk CD. The N-terminal "beta-barrel" domain of 5-lipoxygenase is essential for nuclear membrane translocation[J]. J Biol Chem, 2001, 276:811-818.
[26] Anderson ER, Shah YM. Iron homeostasis in the liver[J]. Compr Physiol, 2013, 3:315-330.
[27] Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload[J]. J Clin Invest, 2005, 115:2180-2186.
[28] Elserag HB. Rising incidence of hepatocellular carcinoma in the United States[J]. N Engl J Med, 1999, 340:745-750.
[29] Yao J, Sun W, Chen J, et al. Advances in the study of structural modifications of multi-target anticancer drug sorafenib[J]. Acta Pharm Sin (药学学报), 2012, 47:1111-1119.
[30] Galmiche A, Ezzoukhry Z, François C, et al. BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma[J]. Mol Cancer Res, 2010, 8:1116-1125.
[31] Shimizu S, Takehara T, Hikita H, et al. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma[J]. Int J Cancer, 2012, 131:548-557.
[32] Chiou JF, Tai CJ, Wang YH, et al. Sorafenib induces preferential apoptotic killing of a drug-and radio-resistant HepG2 cells through a mitochondria-dependent oxidative stress mechanism[J]. Cancer Biol Ther, 2009, 8:1904-1913.
[33] Houessinon A, François C, Sauzay C, et al. Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib[J]. Mol Cancer, 2016, 15:38-48.
[34] Sun X, Niu X, Chen R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis[J]. Hepatology, 2016, 64:488-500.
[35] Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib[J]. Int J Cancer, 2013, 133:1732-1742.
[36] Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63:173-184.
[37] Knudsen ES, Knudsen KE. Tailoring to RB:tumour suppressor status and therapeutic response[J]. Nat Rev Cancer, 2008, 8:714-724.
[38] Mayhew CN, Carter SL, Fox SR, et al. RB loss abrogates cell cycle control and genome integrity to promote liver tumorigenesis[J]. Gastroenterology, 2007, 133:976-984.
[39] Louandre C, Marcq I, Bouhlal H, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells[J]. Cancer Lett, 2015, 356:971-977.
[40] Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity[J]. Clin Liver Dis, 2013, 17:587-607.
[41] Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure:results of a United States multicenter, prospective study[J]. Hepatology, 2005, 42:1364-1372.
[42] Hu J, Kholmukhamedov A, Lindsey CC, et al. Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury:protection by starch-desferal and minocycline[J]. Free Radic Biol Med, 2016, 97:418-426.
[43] Torii S, Shintoku R, Kubota C, et al. An essential role for functional lysosomes in ferroptosis of cancer cells[J]. Biochem J, 2016, 473:769-777.
[44] Li Y, Dai GW, Li Y, et al. Effect of bicyclol on acetaminophen-induced hepatotoxicity:energetic metabolism and mitochondrial injury in acetaminophen-intoxicated mice[J]. Acta Pharm Sin (药学学报), 2001, 36:723-726.
[45] Lőrincz T, Jemnitz K, Kardon T, et al. Ferroptosis is involved in acetaminophen induced cell death[J]. Pathol Oncol Res, 2015, 21:1115-1121.
[46] Wree A, Eguchi A, Mcgeough MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice[J]. Hepatology, 2014, 59:898-910.
[47] Wang S, Pacher P, De Lisle RC, et al. A mechanistic review of cell death in alcohol-induced liver injury[J]. Alcohol Clin Exp Res, 2016, 40:1215-1223.
[48] Kohgo Y, Ohtake T, Ikuta K, et al. Iron accumulation in alcoholic liver diseases[J]. Alcohol Clin Exp Res, 2005, 29:189S-193S.
[49] Corradini E, Pietrangelo A. Iron and steatohepatitis[J]. J Gastroenterol Hepatol, 2012, 27:42-46.
[50] Wang H, An P, Xie E, et al. Characterization of ferroptosis in murine models of hemochromatosis[J]. Hepatology, 2017, 66:449-465.
[51] Ji C. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries[J]. Biochem Res Int, 2012, 2012:216450.
[52] Cederbaum AI. Cytochrome P4502E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells[J]. J Gastroenterol Hepatol, 2006, 21:S22-S25.
[53] Louvet A, Mathurin P. Alcoholic liver disease:mechanisms of injury and targeted treatment[J]. Nat Rev Gastroenterol Hepatol, 2015, 12:231-242.
[54] Philippe MA, Ruddell RG, Ramm GA. Role of iron in hepatic fibrosis:one piece in the puzzle[J]. World J Gastroenterol, 2007, 13:4746-4754.
[55] Hirano A, Kaplowitz N, Tsukamoto H, et al. Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats[J]. Hepatology, 1992, 16:1423-1427.
[56] Subramaniam N. Pathology of hepatic iron overload[J]. World J Gastroenterol, 2007, 13:4755-4760.
[57] Fernándezreal JM, Lópezbermejo A, Ricart W. Cross-talk between iron metabolism and diabetes[J]. Diabetes, 2002, 51:2348-2354.
[58] Bekri S, Gual P, Anty R, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH[J]. Gastroenterology, 2006, 131:788-796.
[59] Sorrentino P, D'Angelo S, Ferbo U, et al. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis[J]. J Hepatol, 2009, 50:351-357.
[60] Anstee QM, Daly AK, Day CP. Genetic modifiers of non-alcoholic fatty liver disease progression[J]. Biochim Biophys Acta, 2011, 1812:1557-1566.
[61] Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease:biochemical, metabolic, and clinical implications[J]. Hepatology, 2010, 51:679-689.
[62] Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis[J]. Semin Liver Dis, 1996, 16:13-30.
[63] Xie Y, Song X, Sun X, et al. Identification of baicalein as a ferroptosis inhibitor by natural product library screening[J]. Biochem Biophys Res Commun, 2016, 473:775-780.
[64] Eling N, Reuter L, Hazin J, et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells[J]. Oncoscience, 2015, 2:517-532.