An iron delivery pathway mediated by a lipocalin Original paper
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Dr. Umar
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Dr. Umar
Read MoreClinical Pharmacist and Clinical Pharmacy Master’s candidate focused on antibiotic stewardship, AI-driven pharmacy practice, and research that strengthens safe and effective medication use. Experience spans digital health research with Bloomsbury Health (London), pharmacovigilance in patient support programs, and behavioral approaches to mental health care. Published work includes studies on antibiotic use and awareness, AI applications in medicine, postpartum depression management, and patient safety reporting. Developer of an AI-based clinical decision support system designed to enhance antimicrobial stewardship and optimize therapeutic outcomes.
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Dr. Umar
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Researched by:
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Dr. Umar
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Dr. Umar
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Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Dr. Umar
What was studied?
This study examined an alternative, transferrin-independent iron delivery pathway mediated by 24p3/Ngal (neutrophil gelatinase–associated lipocalin), showing that this lipocalin can bind iron (likely via a siderophore-like cofactor) and deliver it into cells through receptor-mediated endocytosis. The authors originally purified 24p3 from ureteric bud (UB)–conditioned media as an epithelial inducer during kidney development and then demonstrated that the same protein functions as an iron-trafficking carrier with distinct intracellular routing compared with transferrin. Mechanistically, the work focused on how 24p3/Ngal enters cells, traffics through acidic vesicles, releases iron into the cytoplasm, and triggers canonical iron-responsive gene programs. These experiments were designed to explain how developing organs—particularly embryonic kidney—acquire iron even when classic transferrin pathways are absent or insufficient.
Who was studied?
No human patient cohort was studied. Instead, the investigators used embryonic rodent kidney tissues (rat metanephric mesenchyme and developing rat kidneys, including E13–E15 stages) and multiple renal cell culture models representing different renal lineages and developmental states. These included mouse UB cells (embryonic collecting duct lineage), human Wilms tumor kidney epithelial cells, MDCK cells (canine collecting duct epithelium), rat embryonic renal epithelial cells (7.1), and mouse kidney stromal cells (BF-2/Foxd1+). This panel allowed the authors to compare uptake and trafficking of iron-loaded 24p3/Ngal versus transferrin across epithelial and stromal contexts, and to map stage-specific uptake patterns within the developing kidney.
Most important findings
The key finding is that 24p3/Ngal is an iron-trafficking protein: UB cells labeled with radioactive iron produced iron-associated 24p3, and purified 24p3/Ngal delivered iron into diverse renal cells in a time- and temperature-dependent, saturable manner consistent with receptor-mediated uptake. Unlike transferrin, 24p3/Ngal trafficked largely to acidic vesicles (supported by DAMP colocalization) and showed a more acid-shifted pH requirement for iron release; iron delivery was blocked by bafilomycin, indicating dependence on endosomal acidification. 24p3/Ngal vesicles partially colocalized with DMT1 (NRAMP2), implying a route for released iron to enter the cytosolic pool. Critically, iron-loaded Ngal regulated iron-responsive genes in the expected direction—increasing ferritin and decreasing transferrin receptor 1—demonstrating functional cytosolic iron delivery. Developmentally, transferrin and 24p3 targeted different cell populations in embryonic kidney: transferrin was enriched in late epithelial progenitors and their tubular progeny, whereas 24p3/Ngal targeted peripheral early epithelial precursors and stroma, supporting a model of stage-specific iron provisioning during nephrogenesis.
| Microbiome-signature–relevant signal | Study-specific association (non-microbial host pathway) |
|---|---|
| Lipocalin family marker | 24p3/Ngal acts as an iron carrier and developmental regulator |
| Iron availability response | Ferritin up, transferrin receptor 1 down after iron-loaded Ngal |
| Endosomal/acidification dependency | Bafilomycin blocks iron delivery from Ngal (acidic vesicle requirement) |
| Siderophore-like mechanism concept | Iron binding likely involves an enterobactin-like cofactor bound to Ngal |
Key implications
Clinically, this work positions 24p3/Ngal (now widely recognized as NGAL, a biomarker in kidney injury) as a functional iron shuttle rather than merely an inflammation-associated protein. Although this paper is not a microbiome study, it has strong microbiome-signature relevance because it provides a mechanistic foundation for how a host lipocalin can bind siderophore-like iron chelators and traffic iron—an axis central to host–microbe competition for nutrients. The implication for translational microbiome databases is that elevated NGAL/24p3 may reflect not only epithelial stress but also shifts in iron handling and siderophore-related biology, helping stratify host states where microbial iron acquisition pressures (and host nutritional immunity responses) could shape microbial community structure and function.
Citation
Yang J, Goetz D, Li JY, et al. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002;10(5):1045-1056.