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Identification and characterization of novel hepcidin mimetics that modulate ferroportin function
Cristina Castillo1, Raha Zaman1, Marwa O El-Derany1,2
1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
Blood. Red Cells & Iron
|July 17, 2026
Summary
Researchers discovered a small molecule, schisandrin B (SchB), that mimics the iron-regulating hormone hepcidin. This orally available compound effectively reduces iron overload in mice by targeting the hepcidin-ferroportin pathway.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Hepcidin regulates systemic iron homeostasis by degrading ferroportin (FPN).
- Low hepcidin levels cause iron overload disorders.
- Current treatments for iron overload have limitations including toxicity and poor oral bioavailability.
Purpose of the Study:
- To identify small-molecule hepcidin mimetics.
- To restore physiological control of iron export via the hepcidin-FPN pathway.
- To develop orally bioavailable treatments for iron overload disorders.
Main Methods:
- High-throughput screening of 26,843 compounds using FPN-GFP reporter cell lines.
- Assessed compound activity by measuring cellular growth and ferritin levels.
- Investigated compound interaction with FPN and hepcidin binding.
- Administered compounds orally to hepcidin knockout mice.
Main Results:
- Schisandrin A (SchA), SchB, and hycanthone mimicked hepcidin activity.
- These compounds induced FPN lysosomal degradation and inhibited hepcidin binding to FPN.
- Oral SchB administration reduced iron burden and FPN levels in mice.
- SchB demonstrated potent, orally bioavailable hepcidin-mimetic activity.
Conclusions:
- Schisandrin B is a potent, orally bioavailable small-molecule hepcidin mimetic.
- Pharmacologic activation of the hepcidin-FPN axis with small molecules is feasible.
- SchB offers a potential new therapeutic strategy for iron overload disorders.
