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Until several years ago, iron transport was thought to be relatively simple and straightforward. Until the discovery of lipocalin, iron delivery to tissues was considered to be exclusively mediated by transferrin and its receptor. Lipocalin, a neutrophil-secreted protein, was found to be an iron-binding protein able to remove iron from bacterial siderophores1 . Siderophores are used by some microorganisms to steal iron from the transferrin of their mammalian hosts, and lipocalin was found to be an iron-binding protein able to bind bacterial siderophores1 , thus denying essential iron to bacteria. In addition, lipocalin provided an answer to the mystery of the non-lethality of atransferrinemia, since lipocalin was shown to transport iron from mammalian epithelial and ureteric bud cells2 and deliver it to a different cellular endosome than that of transferrin and its receptor cellular pathway3 . In the first manuscript, Devireddy and colleagues show that lipocalin is even more multifaceted, as it appears to be involved in the apoptotic pathway. The authors show that at least some of the anti-apoptotic properties of bcr/abl are mediated by lipocalin. In the second manuscript, Berger and colleagues, using a lipocalin knockout mouse (Lcn-/-), further specify lipocalin’s role in response to various pro-apoptotic stimuli. They reproduced the previously reported role of lipocalin in innate immune protection against E.coli4 , but they show that lipocalin’s role in apoptosis does not extend to other pro-apoptotic stimuli, as lipocalin did not prevent tissue ischemic injury.

Clearly, more remains to be learned about lipocalin’s role in innate immunity, but these new discoveries of lipocalin’s function raise important concerns for everyday medical practices. The injudicious use of iron for any undiagnosed anemia may worsen the outcome of bacterial and mycobacterial infections4,5 . In contrast, the iron chelator desferroxamine can be used as a source of iron by fungus from the Rhizopis family with at times disastrous clinical outcomes5 . In addition to the well-known Warburg effect mediated by HIF-1α modulation by iron containing proline hydroxylases and the effect of iron chelators on cancer progression6 , lipocalin’s effect on cancerogenesis reveals yet another mechanism of cancer outcome influenced by iron manipulation. A new role for iron in cancerogenesis has emerged, namely the lipocalin-iron pathway that directly regulates apoptosis of certain cancers.

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Competing Interests

Drs. Necas and Prchal indicated no relevant conflicts of interest.