{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T02:54:29Z","timestamp":1776653669891,"version":"3.51.2"},"reference-count":141,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T00:00:00Z","timestamp":1646784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/50006\/2020 | UIDP\/50006\/2020"],"award-info":[{"award-number":["UIDB\/50006\/2020 | UIDP\/50006\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In healthy individuals, virtually all blood plasma iron is bound by transferrin. However, in several diseases and clinical conditions, hazardous non-transferrin-bound iron (NTBI) species occur. NTBI represents a potentially toxic iron form, being a direct cause of oxidative stress in the circulating compartment and tissue iron loading. The accumulation of these species can cause cellular damage in several organs, namely, the liver, spleen, and heart. Despite its pathophysiological relevance, the chemical nature of NTBI remains elusive. This has precluded its use as a clinical biochemical marker and the development of targeted therapies. Herein, we make a critical assessment of the current knowledge of NTBI speciation. The currently accepted hypotheses suggest that NTBI is mostly iron bound to citric acid and iron bound to serum albumin, but the chemistry of this system remains fuzzy. We explore the complex chemistry of iron complexation by citric acid and its implications towards NTBI reactivity. Further, the ability of albumin to bind iron is revised and the role of protein post-translational modifications on iron binding is discussed. The characterization of the NTBI species structure may be the starting point for the development of a standardized analytical assay, the better understanding of these species\u2019 reactivity or the identification of NTBI uptake mechanisms by different cell types, and finally, to the development of new therapies.<\/jats:p>","DOI":"10.3390\/molecules27061784","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T11:30:38Z","timestamp":1646825438000},"page":"1784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The (Bio)Chemistry of Non-Transferrin-Bound Iron"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-7714","authenticated-orcid":false,"given":"Andr\u00e9 M. N.","family":"Silva","sequence":"first","affiliation":[{"name":"LAQV-REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, Rua do Campo Alegre s\/n, 4169-007 Porto, Portugal"}]},{"given":"Maria","family":"Rangel","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade to Porto, Rua Jorge Viterbo Ferreira N228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Crichton, R.R. (2001). The Importance of Iron for Biological Systems. Inorganic Biochemistry of Iron Metabolism, John Wiley & Sons, Ltd.. 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