{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:45:26Z","timestamp":1791830726270,"version":"4.3.4"},"reference-count":81,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RC 2024-RC 2025"],"award-info":[{"award-number":["RC 2024-RC 2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Plasma non-transferrin-bound iron (NTBI) comprises multiple subspecies, classified by their composition, chemical reactivity, and susceptibility to chelation. The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI). The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels. Several mechanisms have been proposed for their cellular entry, including the hijacking of divalent metal transporters and passive diffusion. This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart. NTBI and LPI bypassing normal cellular control mechanisms can rapidly exceed the cell\u2019s capacity to safely store excess iron, leading to toxicity. Both NTBI and LPI contribute to oxidative stress by participating in free-radical-generating reactions. However, LPI concentration in the bloodstream may be differentially affected by the mode and extent of iron overload, the presence of residual serum iron-binding activity, and the antioxidant capacity of individual sera. In summary, both NTBI and LPI contribute to iron-mediated toxicity but differ in terms of reactivity, availability, and pathogenic potential depending on the pathophysiological conditions that influence the degree of toxicity.<\/jats:p>","DOI":"10.3390\/ijms26136433","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T03:47:26Z","timestamp":1751600846000},"page":"6433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2008-3187","authenticated-orcid":false,"given":"Lorena","family":"Duca","sequence":"first","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-1349","authenticated-orcid":false,"given":"Elena","family":"Di Pierro","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Scaramellini","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Dipartimento di Scienze Cliniche e di Comunit\u00e0, Dipartimento di Eccellenza 2023\u20132027, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-3374","authenticated-orcid":false,"given":"Francesca","family":"Granata","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-5730","authenticated-orcid":false,"given":"Giovanna","family":"Graziadei","sequence":"additional","affiliation":[{"name":"SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.immuni.2016.02.016","article-title":"Macrophages and Iron metabolism","volume":"44","author":"Soares","year":"2016","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3389\/fphar.2014.00045","article-title":"Labile iron in cells and body fluids: Physiology, pathology, and pharmacology","volume":"5","author":"Cabantchik","year":"2014","journal-title":"Front. 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