U.S. Department of Health and Human Services

Potential New Prevention or Treatment Approach to Iron Overload

​Mini-hepcidins may provide beneit to people at risk for iron overload or people with iron overload. Hepcidin, a hormone produced by the liver, is the master regulator of iron balance in humans and other mammals. Hepcidin inhibits iron transport from cells in the intestine by binding to the iron channel, ferroportin, thereby reducing dietary iron absorption into the body. Insuficient levels of hepcidin cause or contribute to iron overload anemias such as hereditary hemochromatosis. Hepcidin deiciency is the cause of most cases of iron overload in people with hemochromatosis, a disorder in which the body absorbs too much iron and the extra iron builds up in organs. Strategies that increase the effective level of hepcidin might help ameliorate or prevent damage to organs, including the liver, heart, or pancreas for individuals with hemochromatosis and potentially other conditions marked by iron overload.

Building on previous research that demonstrated that miniature forms of hepcidin (fragments from one end of this hormone) could mimic hepcidin activity in mice, the same group of investigators synthesized a number of different versions of miniature hepcidins, tested these to identify an optimized “mini-hepcidin” called “PR65,” and assessed its ability to prevent or treat iron overload in mice. Initially, PR65 was found to have superior potency and long-lasting action compared with natural hepcidin in normal laboratory mice.

Subsequent experiments utilized genetically engineered mice that no longer produced hepcidin. As hepcidin inhibits iron absorption, mice lacking hepcidin would be expected to absorb and store increased levels of iron. These mice were fed an iron-deicient diet for eight weeks and then placed on a diet high in iron for two weeks while simultaneously being given daily injections of either PR65 or control injection (without PR65). Under these conditions, PR65 signiicantly reduced blood iron levels for up to 24 hours. In addition, PR65 prevented iron accumulation in the heart, liver, and blood of mice initially placed on an iron-depletion diet and then challenged with an iron-loading diet. In mice “pre-loaded” with iron using a standard diet, injection of PR65 daily for two weeks signiicantly reduced liver iron content by 20 percent but did not reduce iron content in the heart or blood.

Past investments in basic science research provided the foundation for this exciting study. Ongoing research is evaluating this and other promising compounds to effectively combat iron-related blood disorders.

Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins
prevent iron overload in a hepcidin‑deicient mouse model of
severe hemochromatosis. Blood 120: 3829-3836, 2012.