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However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin\/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.<\/jats:p>","DOI":"10.3390\/ijms24043995","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T04:51:46Z","timestamp":1676523106000},"page":"3995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Managing the Dual Nature of Iron to Preserve Health"],"prefix":"10.3390","volume":"24","author":[{"given":"Laura","family":"Silvestri","sequence":"first","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariateresa","family":"Pettinato","sequence":"additional","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Furiosi","sequence":"additional","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Bavuso Volpe","sequence":"additional","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0739-5282","authenticated-orcid":false,"given":"Antonella","family":"Nai","sequence":"additional","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Pagani","sequence":"additional","affiliation":[{"name":"Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3324\/haematol.2019.232124","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume":"105","author":"Camaschella","year":"2020","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.cell.2005.06.025","article-title":"Identification of an Intestinal Heme Transporter","volume":"122","author":"Shayeghi","year":"2005","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1017\/S0007114508066762","article-title":"Haem and folate transport by proton-coupled folate transporter\/haem carrier protein 1 (SLC46A1)","volume":"101","author":"Laftah","year":"2008","journal-title":"Br. 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