Many diseases are caused by deficiencies of iron transport proteins that diminish transmembrane iron flux in distinct sites and directions. Because other iron transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. We discovered the small molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.




Tony Grillo (UIUC)