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Iron is an essential micronutrient for nearly all forms of life. Its capacity to readily gain and lose electrons enables its participation in redox processes that are fundamental to energy production, the preservation of genomic integrity, and the transport of oxygen. Transferrin is an important and well-characterized protein for transporting iron throughout the body. However, individuals with atransferrinemia, a condition marked by a lack of transferrin in blood plasma, are still able to distribute iron to their organs, pointing to alternative iron transport mechanisms. In this paper, the authors define, for the first time in molecular detail, a transferrin-independent iron uptake pathway in mammalian cells that is mediated through the protein glycosylphosphatidylinositol-melanotransferrin (CD228). Their findings reveal potential therapeutic targets for diseases in which iron metabolism is dysregulated, including cancers and neurodegenerative diseases.

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