Abstract��Iron is one of the essential trace elements in the human body, the body adjusts its own iron content to maintain iron balance. Iron imbalance, either iron deficiency or over load can cause variety of diseases. As a small molecule peptide hormones, hepcidin negatively regulates iron metabolism. It has become a new therapeutic target for iron disorder diseases. The structure of hepcidin, its regulation mechanism of iron metabolism, the regulatory mechanism of hepcidin in the body, and related diseases caused by hepcidin imbalance were reviewed. This article also reviewed the types and advances of new drugs targeting hepcidin. Due to the continuous research on hepcidin, a specific targeted therapy for specific molecules in the hepcidin signaling pathway has been gradually developed. Through hepcidin activator or antagonist, it can promote or inhibit the expression of hepcidin, thereby improving or treating disorders related to iron metabolism disorders at the molecular level. Hepcidin itself, hepcidin activator represented by small chemical compounds and siRNA, and hepcidin antagonist represented by heparin derivatives are hopeful new drugs to correct disorders related to iron homeostasis.
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WANG Xiao-xue, CUI Hui-fei. The Development of New Drug Targeting Hepcidin. Chinese Pharmaceutical Journal, 2018, 53(6): 405-410.
KRAUSE A, NEITZ S, MAGERT H J, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity [J]. FEBS Lett, 2000, 480(2-3):147-150.
[2]
PARK C H, VALORE E V, WARING A J, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver [J]. J Biol Chem, 2001, 276(11):7806-7810.
[3]
PIGEON C, ILYIN G, COURSELAUD B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload [J]. J Biol Chem, 2001, 276(11):7811-7819.
[4]
NICOLAS G, BENNOUN M, DEVAUX I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice [J]. P Natl Acad Sci USA, 2001, 98(15):8780-8785.
[5]
WEINSTEIN D A, ROY C N, FLEMING M D, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia:implications for the anemia of chronic disease [J]. Blood, 2002, 100(10):3776-3781.
[6]
GUNSHIN H, MACKENZIE B, BERGER U V, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter [J]. Nature, 1997, 388(6641):482-488.
[7]
HENTZE M W, MUCKENTHALER M U, GALY B, et al. Two to tango:regulation of mammalian iron metabolism [J]. Cell, 2010, 142(1):24-38.
[8]
POSS K D, TONEGAWA S. Heme oxygenase 1 is required for mammalian iron reutilization [J]. P Natl Acad Sci USA, 1997, 94(20):10919-10924.
[9]
CAMASCHELLA C. Iron and hepcidin:a story of recycling and balance [J]. Hematology, 2013, 2013(1):1-8.
[10]
DELABY C, PILARD N, GON ALVES A S, et al. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin [J]. Blood, 2005, 106(12):3979-3984.
[11]
NEMETH E, TUTTLE M S, POWELSON J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization [J]. Sci, 2004, 306(5704):2090-2093.
[12]
LIN L, VALORE E V, NEMETH E, et al. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 [J]. Blood, 2007, 110(6):2182-2189.
[13]
GANZ T, NEMETH E. Hepcidin and disorders of iron metabolism [J]. Annual Rev Med, 2011, 62(1):347-360.
[14]
QIAO B, SUGIANTO P, FUNG E, et al. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination [J]. Cell Metab, 2012, 15(6):918-924.
[15]
BABITT J L, HUANG F W, WRIGHTING D M, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression [J]. Nat Gen, 2006, 38(5):531-539.
[16]
KUNINGER D, KUNSHASHIMOTO R, KUZMICKAS R, et al. Complex biosynthesis of the muscle-enriched iron regulator RGMc [J]. J Cell Sci, 2006, 119(Pt 16):3273-3283.
[17]
LIN L, NEMETH E, GOODNOUGH J B, et al. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site [J]. Blood Cells Mol Dis, 2008, 40(1):122-131.
[18]
CANALI S, CORE A B, ZUMBRENNENBULLOUGH K B, et al. Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes:evidence for a role in hepcidin induction by inflammation in male mice [J]. Endocrinology, 2016, 157(3):1146-1162.
[19]
MCMAHON S, GRONDIN F, MCDONALD P P, et al. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1:impact on the bioactivation of proproteins [J]. J Biol Chem, 2005, 280(8):6561-6569.
[20]
LUNDBY C, GASSMANN M, PILEGAARD H. Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions [J]. Eur J Appl Phys, 2006, 96(4):363-369.
[21]
PIETRANGELO A. Hereditary hemochromatosis:pathogenesis, diagnosis, and treatment [J]. Gastroenterol, 2010, 139(2):393-408.
[22]
PIETRANGELO A. Hereditary hemochromatosis-A new look at an old disease [J]. New Engl J Med, 2004, 350(23):2383-2397.
[23]
ENNS C A, AHMED R, ZHANG A S. Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage [J]. J Biol Chem, 2012, 287(42):35104-35117.
[24]
WRIGHTING D M, ANDREWS N C. Interleukin-6 induces hepcidin expression through STAT3 [J]. Blood, 2006, 108(9):3204-3209.
[25]
SEN B, SAIGAL B, PARIKH N, et al. Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding [J]. Cancer Res, 2009, 69(5):1958-1965.
[26]
VERGA FALZACAPPA M V, VUJIC SPASIC M, KESSLER R, et al. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation [J]. Blood, 2007, 109(1):353-358.
[27]
FALZACAPPA M V V, CASANOVAS G, HENTZE M W, et al. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells [J]. J Mol Med, 2008, 86(5):531-540.
[28]
YU P B, HONG C C, SACHIDANANDAN C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism [J]. Nat Chem Biol, 2008, 4(1):33-41.
[29]
SILVESTRI L, GUILLEM F, PAGANI A, et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia [J]. Blood, 2009, 113(22):5605-5608.
[30]
SASU B J, COOKE K S, ARVEDSON T L, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia [J]. Blood, 2010, 115(17):3616-3624.
[31]
XUE Y, XIA S J, ZHANG S H, et al. Heavy iron chelating agent treatment B-the mediterranean anemia Meta analysis of curative effect[J]. Chin Pharm J(�й�ҩѧ��־), 2013, 48(13); 1088-1093.
[32]
RAMOS E, RUCHALA P, GOODNOUGH J B, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis[J]. Blood, 2012, 120(18):3829-3836.
[33]
FUNG E, CHUA K, GANZ T, et al. Thiol-derivatized minihepcidins retain biological activity [J]. Bioorg Med Chem Lett, 2015, 25(4):763-766.
[34]
ZHEN A W, NGUYEN N H, GIBERT Y, et al. The small molecule, genistein, increases hepcidin expression in human hepatocytes [J]. Hepatology, 2013, 58(4):1315-1325.
[35]
BYRNE S L, BUCKETT P D, KIM J, et al. Ferristatin �� promotes degradation of transferrin receptor-1 in vitro and in vivo [J]. PLoS One, 2013, 8(7):e70199-e70210.
[36]
ZHANG M, LIU J, GUO W, et al. Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling [J]. Inter J Mol Med, 2016, 37(5):1379-1388.
[37]
NAI A, PAGANI A, MANDELLI G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of ��-thalassemia [J]. Blood, 2012, 119(21):5021-5029.
[38]
GUO S, CASU C, GARDENGHI S, et al. Reducing TMPRSS6 ameliorates hemochromatosis and ��-thalassemia in mice [J]. J Clin Invest, 2013, 123(4):1531-1541.
[39]
SCHMIDT P J, IVA T, SENDAMARAI A K, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine ��-thalassemia intermedia [J]. Blood, 2013, 121(7):1200-1208.
[40]
MEYNARD D, KAUTZ L, DARNAUD V, et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload [J]. Nat Gen, 2009, 41(4):478-481.
[41]
CORRADINI E, SCHMIDT P J, MEYNARD D, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice [J]. Gastroenterology, 2010, 139(5):1721-1729.
[42]
XIAO J J, KRZYZANSKI W, WANG Y M, et al. Pharmacokinetics of anti-hepcidin monoclonal antibody Ab 12B9m and hepcidin in cynomolgus monkeys [J]. Aaps J, 2010, 12(4):646-657.
[43]
SUN C C, VAJA V, BABITT J L, et al. Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation [J]. Am J Hematol, 2012, 87(4):392-400.
[44]
MACDOUGALL I C. New anemia therapies:translating novel strategies from bench to bedside [J]. Am J Kid Dis Off J Nat Kid Found, 2012, 59(3):444-451.
[45]
SCHWOEBEL F, VAN EIJK L T, ZBORALSKI D, et al. The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys [J]. Blood, 2013, 121(12):2311-2315.
[46]
HASHIZUME M, UCHIYAMA Y, HORAI N, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production [J]. Rheumatol Inter, 2010, 30(7):917-923.
[47]
SONG S N, TOMOSUGI N, KAWABATA H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease [J]. Blood, 2010, 116(18):3627-3634.
[48]
VAN R F, FAYAD L, VOORHEES P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for castleman��s disease [J]. J Clin Oncol Off J Am Soc Clin Oncol, 2010, 28(23):3701-3708.
[49]
THEURL I, SONNWEBER T, SCHROLL A, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats [J]. Blood, 2011, 118(18):4977-4984.
[50]
PREETHNE B, DIETMAR S, LIGUORI M J, et al. Anti-repulsive guidance molecule C (RGMc) antibodies increases serum iron in rats and cynomolgus monkeys by hepcidin downregulation [J]. Aaps J, 2015, 17(4):1-9.
[51]
ASPERTI M, NAGGI A, ESPOSITO E, et al. High sulfation and a high molecular weight are important for anti-hepcidin activity of heparin [J]. Front Pharm, 2015, 6(104):316-322
[52]
FUNG E, NEMETH E. Manipulation of the hepcidin pathway for therapeutic purposes [J]. Haematologica, 2013, 98(11):1667-1676.
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