Researchers identify a potential therapeutic target for cirrhosis and liver inflammation

The RNF41 protein may become a new therapeutic target in the fight against two chronic liver diseases: cirrhosis and liver inflammation. This is the conclusion of a study published in the journal Science translational medicine led by researcher Pedro Melgar-Lesmes, from the Department of Biomedicine at the Faculty of Medicine and Health Sciences at the University of Barcelona.

This study may lead to the design of drugs that increase the production of RNF41 protein in macrophages, defensive cells of the immune system that play a significant role in the response to liver damage and in the development of chronic liver disease.

“This potential therapeutic target represents a new master regulator of the role of macrophages in the control of chronic liver diseases and other diseases characterized by inflammation and fibrosis,” says Melgar-Lesmes.

“Our findings highlight that the regulation of innate immunity, and in particular macrophage activity, is essential to combat liver fibrosis and improve liver regeneration.”

What is the role of the RNF41 protein in liver fibrosis?

The study reveals that the expression of RNF41 – a protein related to inflammatory processes – is lower in macrophages isolated from liver samples from patients with liver cirrhosis, regardless of the origin of the disease. In mice with liver fibrosis, the expression of the protein in liver macrophages is also reduced.

The team found that a prolonged inflammation process in liver macrophage cell cultures leads to a decrease in RNF41 protein. “Therefore, chronic inflammation may be responsible for the reduction of RNF41 in macrophages,” says Melgar-Lesmes.

In mice where RNF41 protein function could be restored, results have shown increased elimination of fibrosis, reduced liver inflammation and increased liver regeneration.

An innovative method

To achieve these results, an innovative methodology based on the use of dendrimer-graphite nanoparticles (DGNP) – molecules with functional properties of interest in biomedicine – designed by the team has been used. In addition, the technique of specific isolation of macrophages using magnetic beads bound to antibodies (MACS) has also been used. This has shown that these nanoparticles are effective in selective gene therapy in inflamed macrophages in fibrotic liver.

In parallel, in vitro studies confirm that if RNF41 protein disappears in macrophages of fibrotic mouse livers, it triggers a storm of inflammatory cytokines leading to increased fibrosis, liver damage and some mortality. “This tells us that RNF41 protein is necessary to overcome fibrosis and chronic inflammation in liver disease,” says Melgar-Lesmes.

The team’s future lines of research will focus on identifying which proteins control the RNF41 protein in macrophages. “This will allow us to design new drugs to increase the expression of this key protein in the regulation of the role of macrophages in inflammation and liver fibrosis,” concludes Melgar-Lesmes.