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Editorials
increased hepcidin expression show a very specific activ- ity (i.e. hepcidin mimetics or ferroportin inhibitors).15,19 In general, these drugs belong to one of four main cate- gories: (i) hepcidin mimetics; (ii) hepcidin inducers; (iii) ferroportin inhibitors; and (iv) erythroferrone inhibitors. TMPRSS6 inhibitors can be defined as hepcidin inducers and/or BMP/SMAD pathway activators.
The ideal drug should be administered orally or injected subcutaneously very infrequently, having a long lifespan and prolonged activity. The drug should also show a large spectrum of activity, so that it can limit iron absorption in disorders such as non-transfusion-dependent thalassemia and HFE-related hemochromatosis, but also in conditions in which iron absorption is further increased (e.g., β-tha- lassemia major), or in which iron absorption needs to be further suppressed to achieve a significant benefit (as in polycythemia vera).15,18,19 The drug should also have no side effects, particularly under conditions of chronic administration. Obviously, low cost of production would also be desirable. Furthermore, and equally important, the drug should have a clear mechanism of action.
The compounds described by Liu and colleagues are derivatives of thiazolidinones, a group of versatile drugs which are also being developed for numerous clinical applications, such as anti-tuberculosis, antimicrobial, anti-cancer, anti-inflammatory, and antiviral agents.20 These new compounds increase expression of hepcidin and improve several parameters (related to both iron overload and anemia) in mice affected by primary and secondary forms of hemochromatosis (Figure 1B).1
In particular, in mice affected by hemochromatosis, the compounds described by Liu and colleagues ameliorated abnormal iron parameters, improved iron overload, and induced iron redistribution from the liver to the spleen. In mice affected by non-transfusion-dependent thalassemia, these compounds also ameliorated iron overload. In addi- tion, as ineffective erythropoiesis was also improved, red blood cell production and hemoglobin levels increased (Figure 1B).
As described in their article, these novel thiazolidinone derivatives appear to act on hepcidin expression through a variety of mechanisms, such as promoting Smad1/5/8 signaling, repressing Erk1/2 phosphorylation and decreas- ing Tmprss6 activity (Figure 1B). Additionally, these com- pounds seemed to target potential erythroid regulators (such as erythroferrone), thereby further contributing to hepcidin upregulation (Figure 1B). However, the target and mechanism of action of these compounds have not been completely elucidated.
Given their many effects, there is some concern that these drugs may be relatively unselective and affect addi- tional targets and pathways. This would be even more relevant if these drugs were to become used in a chronic fashion. Future studies should, therefore, focus on deter- mining how these drugs interact with their target and exclude unwanted effects.
In summary, these novel compounds are very promis-
ing and expand the armamentarium of drugs that could benefit patients affected by disorders in which increased hepcidin expression is desirable. If proven to be safe, selective, and effective, their use will increase the chance that one or more compounds will reach the clinic, while competition between different drugs will likely diminish costs.
References
1. Liu J, Liu W, Liu Y, et al. New thiazolidinones reduce iron overload in mouse models of hereditary hemochromatosis and β-thalassemia. Haematologica. 2019;104(9):1768-1781.
2. Rivella S. Iron metabolism under conditions of ineffective erythro- poiesis in beta-thalassemia. Blood. 2019;133(1):51-58.
3. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for ion metabolism. Cell. 2017;168(3):344-361.
4. Rausa M, Pagani A, Nai A, et al. Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLoS One. 2015;10(4):e0122696.
5. D'Alessio F, Hentze MW, Muckenthaler MU. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J Hepatol. 2012;57(5):1052-1060.
6. Chen H, Choesang T, Li H, et al. Increased hepcidin in transferrin- treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation. Haematologica. 2016;101(3):297-308.
7. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678-684.
8. Sonnweber T, Nachbaur D, Schroll A, et al. Hypoxia induced down- regulation of hepcidin is mediated by platelet derived growth factor BB. Gut. 2014;63(12):1951-1959.
9. Arezes J, Foy N, McHugh K, et al. Erythroferrone inhibits the induc- tion of hepcidin by BMP6. Blood. 2018;132(14):1473-1477.
10. Wahedi M, Wortham AM, Kleven MD, et al. Matriptase-2 suppress- es hepcidin expression by cleaving multiple components of the hep- cidin induction pathway. J Biol Chem. 2017;292(44):18354-18371.
11. Nai A, Rubio A, Campanella A, et al. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood. 2016;127(19):2327-2336.
12. Frydlova J, Rychtarcikova Z, Gurieva I, Vokurka M, Truksa J, Krijt J. Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice. PLoS One. 2017;12(10):e0186844.
13. GardenghiS,MarongiuMF,RamosP,etal.Ineffectiveerythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of fer- roportin. Blood. 2007;109(11):5027-5035.
14. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569-571.
15. CasuC,NemethE,RivellaS.Hepcidinagonistsastherapeutictools. Blood. 2018;131(16):1790-1794.
16. Guerra A, Musallam KM, Taher AT, Rivella S. Emerging therapies. Hematol Oncol Clin North Am. 2018;32(2):343-352.
17. Casu C, Aghajan M, Oikonomidou PR, Guo S, Monia BP, Rivella S. Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia. Haematologica. 2016;101(1):e8-e11.
18. Casu C, Oikonomidou PR, Chen H, et al. Minihepcidin peptides as disease modifiers in mice affected by beta-thalassemia and poly- cythemia vera. Blood. 2016;128(2):265-276.
19. Oikonomidou PR, Casu C, Rivella S. New strategies to target iron metabolism for the treatment of beta thalassemia. Ann N Y Acad Sci. 2016;1368(1):162-168.
20. KaurManjalS,KaurR,BhatiaR,etal.Syntheticandmedicinalperspec- tive of thiazolidinones: a review. Bioorg Chem. 2017;75:406-423.
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