Science 356, 608–616 (2017)

Credit: AAAS

Iron homeostasis requires membrane transporters such as DMT1, mitoferrin, and ferroportin to modulate the movement of iron into and out of cells. Disorders such as anemia are correlated with loss of these transporters, and there are no existing chemical means of restoring transporter function. To address this gap, Grillo et al. used a yeast strain that was defective in the iron-transporting complex FetFtr1 to perform a chemical screen for small-molecule compounds that could mimic the activity of protein channels and restore iron efflux. The natural product hinokitiol, previously known to function as an iron chelator, restored growth in this mutant strain and also rescued iron transport in cell lines deficient in DMT1, mitoferrin, or ferroportin. UV–visible spectroscopy titration analysis revealed that hinokitiol binds iron with high affinity, and hinokitiol treatment of iron-loaded DMT1-deficient cells, which exhibit a buildup of labile iron, promoted iron efflux. Conversely, hinokitiol promoted iron uptake in the presence of high extracellular iron concentrations. Together, these results suggested that the iron flux effects of hinokitiol are proportional to cellular iron gradients. Finally, hinokitiol promoted gut iron absorption and rescued anemia in transporter-deficient animal models, offering an intriguing new tool for restoring iron transport.