Small molecule transports iron in mice and human cells to treat certain forms of anemia

CHAMPAIGN, Ill. – A naturally occurring small molecule derived from a cypress tree can transport iron into live mice and human cells lacking the protein that normally does the job, facilitating iron accumulation in the liver and restoring hemoglobin and production of red blood cells, a new study found.

Coming from a collaboration between researchers from the University of Illinois Urbana Champaign, the University of Michigan, Ann Arbor and the University of Modena in Italy, the study demonstrated that the small molecule hinokitiol could potentially function as a “molecular prosthesis” when the iron-transporting protein ferroportin is missing or defective, providing a potential treatment route for ferroportin disease and certain types of anemia.

“This is a truly striking demonstration in a whole animal model that an imperfect mimic of a missing protein can restore physiology, acting as a molecular-scale prosthesis,” said the co-lead of the study. ‘study. Dr. Martin D. BurkeProfessor of chemistry at Illinois and a member of Carle Illinois College of Medicine, as well as a doctor. “The implications are really quite broad compared to other diseases caused by loss of protein function.”

Ferroportin is a protein that forms a channel to transport iron in and out of cells. Ferroportin deficiency can be due to a genetic mutation or caused by inflammation or infection. Patients without protein have excess iron buildup in the liver, spleen, and bone marrow, particularly in a type of cell called a macrophage. Macrophages in the liver chew up old red blood cells and transport the iron they contain to recycle it into new red blood cells. However, without ferroportin, iron accumulates inside cells and cannot be recycled, Burke said.

Removing blood from the body, as is usually done for other illnesses caused by iron buildup, is not an effective treatment because the buildup is localized and blood iron levels are actually low. , said study co-author Dr. Antonello Pietrangelo, Professor. of medicine in Modena. Pietrangelo was the first to identify genetic ferroportin disease in patients as distinct from a more well-documented form of iron overload that causes iron to build up in blood serum.

Burke’s group in Illinois detailed hinokitiol’s ability to move iron across cell membranes and correct anemia in zebrafish in 2017, establishing it as a potential candidate for therapeutic application. . In the new study, published in the journal PNAS, researchers investigated the action of hinokitiol in live mice lacking the ferroportin gene, as well as in macrophages from patients with ferroportin disease.

Michigan Professor Young-Ah Seo’s research group, which studies genetic iron and manganese disorders, provided proof of concept that hinokitiol could improve anemia in mice.

“We saw that mice treated with hinokitiol reduced iron accumulation in the liver and improved hemoglobin and red blood cell production,” said Seo, professor of nutritional biochemistry and co-senior author of the study. study. “These results suggest that hinokitiol may deliver iron from the liver to red blood cells and thereby improve hemoglobin in mice.”

The researchers noted that although iron distribution was still lower than normal in mice treated with hinokitiol, hemoglobin and red blood cell levels were enhanced to normal. This indicates that the small molecule, although not a perfect replacement for ferroportin, could effectively treat anemia, said Stella Ekaputri, graduate student from Illinois and first author of the study.

“In healthy organisms, there is a threshold of functionality. Our goal is to give a little push to reach the threshold,” Ekaputri said. “Even if our small molecule is not perfect, homeostasis is found for hemoglobin. A little push is all it takes to overcome the bottlenecks created by ferroportin deficiency.

Researchers dug deeper to understand the mechanisms of how hinokitiol enhanced iron transport and hemoglobin production in mice. They found that hinokitiol bound to iron in macrophages where it had accumulated and transported iron out of cells. Then the hinokitiol transferred the iron to another protein, transferrin, which reinserted the iron into the normal cycle of hemoglobin production, the researchers found.

Researchers verified that hinokitiol works the same way in human cells by studying its action in liver macrophages from human patients with ferroportin disease.

“Using macrophages from our patients, we were able to show that hinokitiol can very effectively remove ‘free iron’ as well as iron stores from macrophages of patients with different mutations,” Pietrangelo said. “This, combined with data in mice that show hinokitiol is also effective in vivo, opens up an entirely new avenue for the treatment of this disorder.”

The researchers are working with the company Kinesid Therapeutics, founded by Burke, to facilitate further work towards the clinical application of hinokitiol or its derivatives.

The National Institutes of Health supported this work.