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Its physiological importance is underscored by atransferrinemia, a rare disorder in which individuals lacking plasma transferrin nonetheless retain the capacity to distribute dietary iron to essential organs, implying the presence of compensatory iron transport routes. Melanotransferrin (MFI2; also designated p97 or CD228) is an evolutionarily conserved iron-binding protein that exists in both a secreted form and a glycosylphosphatidylinositol (GPI)-anchored membrane-bound form, suggesting a fundamental role in iron homeostasis. In mammals, the secreted isoform mediates iron transport across the blood\u2013brain barrier, whereas GPI-anchored MFI2 is expressed by microglia in proximity to \u03b2-amyloid plaques in Alzheimer\u2019s disease, implicating it in neuroinflammatory processes. Moreover, it is also recognized as a tumor-associated antigen in melanoma, indicating a potential role in tumor progression. In the present study, we delineate a previously uncharacterized NTBI internalization pathway mediated by GPI-MFI2. Using human melanoma cells, we demonstrate that GPI-MFI2, together with its bound iron, undergoes caveolae-dependent internalization followed by trafficking through a Rab5-mediated endosomal pathway. The internalized iron is subsequently trafficked to ferritin, underscoring its functional importance in maintaining intracellular iron stores. These findings establish the first molecularly defined pathway for transferrin-independent iron uptake in mammalian cells, providing a framework to interrogate MFI2\u2019s role in iron mobilization and dysregulation in neurodegeneration and cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03043-9","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T06:35:20Z","timestamp":1776407720000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lipid-anchored melanotransferrin mediates transferrin-independent iron uptake and ferritin storage in mammals"],"prefix":"10.1038","volume":"12","author":[{"given":"Mei Mei","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline W. 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