Researchers have unveiled the RNF41 protein as a potential new therapeutic target in the battle against two chronic liver diseases: cirrhosis and liver inflammation. The study, led by researcher Pedro Melgar-Lesmes from the Department of Biomedicine at the University of Barcelona, has opened new doors to understanding liver disease and developing targeted treatments. The findings were published in the journal Science Translational Medicine.
The study focuses on the role of the Ring finger protein 41 (RNF41), which negatively regulates proinflammatory cytokines and receptors. The precise role of macrophage RNF41 in liver cirrhosis was previously unknown. The team discovered that RNF41 expression is down-regulated in macrophages recruited to the liver in both mice and human patients with cirrhosis. Prolonged inflammation has been found to progressively reduce macrophage RNF41 expression.
The research also includes the design of a macrophage-selective gene therapy with dendrimer-graphite nanoparticles (DGNPs) to explore the effects of macrophage RNF41 restoration and depletion in liver fibrosis and regeneration. The results revealed that RNF41 expression induced by DGNP-conjugated plasmids ameliorated liver fibrosis, reduced liver injury, and stimulated hepatic regeneration in fibrotic mice with or without hepatectomy. These therapeutic effects were mainly mediated by the induction of insulin-like growth factor.
Conversely, depletion of macrophage RNF41 worsened inflammation, fibrosis, hepatic damage, and survival, highlighting the critical role of this protein in the control of hepatic inflammation, fibrosis, and regeneration.
The study could lead to the design of drugs that enhance the production of RNF41 protein in macrophages, the defensive cells of the immune system that play an essential role in liver damage response and chronic liver disease progression.
Pedro Melgar-Lesmes, a member of various renowned research institutes including IDIBAPS, CIBEREHD, and MIT, emphasised the importance of this discovery: “This potential therapeutic target represents a new master regulator of the role of macrophages in the control of chronic liver diseases and other diseases characterised by inflammation and fibrosis.”
An innovative methodology involving dendrimer-graphite nanoparticles (DGNPs) and specific isolation of macrophages using magnetic spheres bound to antibodies (MACS) was used to achieve these results. This demonstrated that the nanoparticles are effective in selective gene therapy in inflamed macrophages in fibrotic liver.
In vitro studies also confirmed 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”, explained Melgar-Lesmes.
The team’s future research will focus on identifying the proteins that control the RNF41 protein in macrophages. This could allow for the design of new drugs to increase the expression of this vital protein in macrophage regulation.
The study marks a significant step forward in the field of hepatic research. By identifying and exploring the RNF41 protein’s role in liver fibrosis and inflammation, the researchers have provided a rationale for therapeutic strategies in chronic liver disease and potentially other inflammation and fibrosis-related diseases.
The breakthrough paves the way for new treatments that could have a profound impact on patients suffering from chronic liver conditions, offering hope for more effective interventions and improved quality of life. It underscores the importance of understanding the complex roles that specific proteins play in disease processes and highlights the potential for targeted, innovative therapies in managing chronic liver diseases.
