Identification and characterization of novel hepcidin mimetics that modulate ferroportin function

- Discovery of small-molecule hepcidin mimetics that engage the canonical ferroportin-hepcidin binding interface. - Demonstration that oral schisandrin B restores systemic iron homeostasis in vivo. Hepcidin maintains systemic iron homeostasis by binding the iron exporter ferroportin and inducing its lysosomal degradation. Inappropriately low hepcidin levels are the primary cause of most iron overload disorders. Existing treatments, such as phlebotomy, iron chelation, and peptide-based hepcidin agonists, are constrained by toxicity, poor tolerability, and lack of oral bioavailability. To discover small-molecule hepcidin mimetics capable of restoring physiological control of iron export through the endogenous hepcidin–FPN pathway, we performed high-throughput screening of 26,843 compounds using doxycycline-inducible FPN–GFP reporter cell lines. Three compounds, Schisandrin A, Schisandrin B, and Hycanthone recapitulated hepcidin activity by restoring cellular growth and ferritin levels in FPN-overexpressing cells. These compounds required canonical hepcidin-interacting residues on FPN, promoted lysosomal degradation, and competitively inhibited binding of biotinylated hepcidin to FPN. In hepatocyte-specific hepcidin knockout mice, oral administration of Schisandrin B reduced hepatic iron burden and decreased FPN abundance in the liver, spleen, and duodenum. Together, these findings identify Schisandrin B as a potent, orally bioavailable small-molecule hepcidin mimetic that attenuates iron overload in vivo, establishing proof of concept that pharmacologic activation of the hepcidin–FPN axis can be achieved with small molecules.