Functional inactivation of duodenal ferroportin by hepcidin drives iron-dependent degradation of DMT1 in lysosomes
Bibliographic record
Abstract
Abstract Hepcidin regulates systemic iron homeostasis by inhibiting iron absorption and recycling through degradation of the iron exporter ferroportin in enterocytes and macrophages. While its effects on macrophages are well characterized, ferroportin regulation in duodenal enterocytes remains less understood. Several studies suggest that duodenal ferroportin is relatively resistant to hepcidin, implying tissue-specific regulatory mechanisms. To investigate this, we used wild-type and hepcidin-deficient Hjv⁻/⁻ mice, a model of hemochromatosis. Synthetic hepcidin administration significantly reduced plasma iron and ferroportin levels in the spleen and liver. In duodenal enterocytes, hepcidin decreased ferroportin and apical divalent metal transporter 1 (DMT1) in wild-type mice. In Hjv⁻/⁻ animals, where both transporters are overexpressed, hepcidin suppressed DMT1 but not ferroportin, yet duodenal iron levels increased—indicating functional ferroportin inactivation. This DMT1 suppression was reproduced in murine intestinal organoids treated with hepcidin or iron, regardless of ferroportin degradation. Short-term high-iron diet in wild-type mice or high-dose hepcidin in Hjv⁻/⁻ mice led to duodenal iron accumulation and degradation of both transporters. Notably, DMT1 (but not ferroportin) degradation was partially rescued by the lysosomal inhibitor chloroquine. These findings demonstrate that hepcidin can degrade duodenal ferroportin under physiological expression, but higher doses are needed when it is overexpressed. Even when hepcidin fails to degrade ferroportin, it can still occlude its iron export channel, leading to intracellular iron accumulation and iron-dependent lysosomal degradation of DMT1. Thus, hepcidin controls iron absorption through dual targeting of duodenal iron transporters via distinct mechanisms: direct functional inactivation of ferroportin that indirectly triggers DMT1 degradation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".