| Gene | SLC40A1 |
| UniProt | [Q9NP59](https://www.uniprot.org/uniprot/Q9NP59) |
| Molecular Weight | 70 kDa |
| Subcellular Localization | Plasma membrane, Endosomes |
| PDB Structures | [6VYH](https://www.rcsb.org/structure/6VYH) (zebrafish) |
| Aliases | FPN, IREG1, MTP1, SLC40A1 |
Ferroportin (SLC40A1), also known as IREG1 or MTP1, is the sole known mammalian iron exporter responsible for transporting ferrous iron (Fe²⁺) out of cells. Working in concert with its regulatory partner hepcidin, ferroportin plays a central role in systemic iron homeostasis and is increasingly implicated in neurodegenerative diseases where iron export dysfunction contributes to pathological iron accumulation.[1]
Ferroportin is a 571-amino acid multi-pass transmembrane protein:[2]
Structural features:
The cryo-EM structure (from zebrafish) reveals:
Ferroportin serves as the cellular iron export channel:[3]
Iron export pathway:
Hepcidin regulation:
Cellular distribution:
Transport mechanism:
Fe²⁺ (intracellular) → Fe²⁺ (extracellular)
Coupled with H⁺ movement (antiport)
Ferroportin dysfunction is directly implicated in NBIA disorders:[4]
Ferroportin Disease (Type 4 Hemochromatosis):
Aceruloplasminemia:
Ferroportin's role in PD iron accumulation:[6]
Mechanistic model:
Aging/α-Synuclein → Hepcidin ↑ → Ferroportin degradation →
Iron export ↓ → Iron accumulation → Fenton chemistry → Neuron death
Ferroportin dysfunction in AD:[7]
Strategies to preserve ferroportin function:[8]
| Strategy | Mechanism | Status |
|---|---|---|
| Anti-hepcidin antibodies | Block hepcidin-ferroportin binding | Clinical trials (anemia) |
| Hepcidin mimetics | Promote ferroportin degradation | Research (iron overload) |
| Small molecule antagonists | Inhibit hepcidin synthesis | Preclinical |
| siRNA/shRNA | Reduce hepcidin production | Research |
Most promising approaches combine:
| Interacting Partner | Function | Relevance |
|---|---|---|
| Hepcidin | Regulatory hormone | Internalization and degradation |
| Ceruloplasmin | Ferroxidase (CNS) | Iron oxidation upon export |
| Hephaestin | Ferroxidase (enterocytes) | Dietary iron export |
| DMT1 | Iron importer | Opposite direction of transport |
| Transferrin | Iron transport protein | Accepts exported iron |
Abboud and Haile, A novel mammalian iron-regulated protein (2000) — Blood. Discovery of ferroportin as the iron exporter.
Nemeth et al., Hepcidin regulates cellular iron efflux (2004) — Science. Establishes hepcidin-ferroportin regulatory axis.
Miyajima et al., Ceruloplasmin and ferroportin in neurodegeneration (2021) — Reviews ferroportin-ceruloplasmin coupling in CNS.
Raha et al., Ferroportin and iron in neurodegeneration (2020) — Comprehensive review of ferroportin in neurodegenerative diseases.
Tan G, et al., Hepcidin and ferroportin in Parkinson's disease (2022) — Links hepcidin-ferroportin axis to PD iron accumulation.
McKie AT, et al. [A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation](https://doi.org/10.1016/S1097-2765(00). Molecular Cell. 2000. ↩︎
Dautry-Varsat A, et al. The structure of ferroportin. Cell. 2020. ↩︎
Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science. 2012. ↩︎
Levi S, et al. Neurodegeneration with brain iron accumulation disorders: valuable models aimed at understanding iron dyshomeostasis. Frontiers in Neuroscience. 2021. ↩︎
Miyajima H. Aceruloplasminemia. Neuropathology. 2015. ↩︎
Raha AA, et al. The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease. Acta Neuropathologica Communications. 2013. ↩︎
Raha AA, et al. Plasma and brain levels of hepcidin and ferroportin in Alzheimer's disease. Journal of Alzheimer's Disease. 2020. ↩︎
Sun CC, et al. Hepcidin: a promising therapeutic target for iron disorders. Drug Discovery Today. 2012. ↩︎