LAUSR

Significance Iron misdistribution underlies various diseases, ranging from anemia to neurodegeneration, but approaches to addressing this general problem are lacking. We recently reported that a small molecule natural product, hinokitiol, is capable of restoring hemoglobinization in various animal models with missing iron transporters. We now show that hinokitiol is capable of redistributing iron systemically, which in turn restores iron homeostasis in ferroportin-deficient mice and in primary macrophages derived from patients with ferroportin disease. We also elucidated the stepwise mechanism of hinokitiol-mediated iron redistribution and physiological restoration. Together, these results provide foundational support for using a molecular prosthetics approach for better understanding and possibly treating iron misdistribution.