Characterized by the accumulation of fat in the liver and often associated with type 2 diabetes, hypertension and high blood lipids, NAFLD has become a global threat. It is estimated that in wealthy countries, 30-40% of adults are affected, with around 20% of these patients having a more advanced stage called non-alcoholic steatohepatitis, or NASH, a condition characterized by inflammation of the liver and which can progress to fibrosis. advanced (cirrhosis) and liver failure. NASH is also a cause of liver cancer. Caused by the accumulation of scars, many teams are working on finding a way to block fibrosis to prevent these liver complications.
A new class of drugs against fibrosis
Using advanced technologies including mononuclear sequencing and 3D imaging, this research conducted on samples of human liver tissue taken from 9 patients with non-alcoholic steatohepatitis and from mice, allows for the first time to characterize the main hepatic scar-producing cells or fibrosis of the liver. These analyzes identify a shared number of 68 possible target pairs for both research, in vitro and in vivo.
These new data also suggest that a drug candidate could be effective in the treatment of non-alcoholic fatty liver disease (NAFLD). It is an anticancer drug that targets one of the identified pairs of proteins.
A cell-to-cell communication network resulting in scars
This is essentially the discovery of the Icahn School team, a cellular network that induces fibrosis as liver disease progresses. Lead author Dr. Scott L. Friedman, Professor of Medicine and Head of the Department of Liver Diseases at the Icahn School explains, “By combining this novel approach to 3D liver imaging and the analysis of ‘gene expression in liver cells, we gain insight into how these cells generate scarring as liver disease progresses to advanced stages’: stellate cells or hepatic stellate cells develop a dense network, or meshwork , which promotes these 68 unique and previously unidentified 2-protein interaction pairs.
A pair of proteins, NTF3-NTRK3 particularly involved: a molecule already developed to block NTRK3 in human cancers appears to be a promising drug candidate to fight liver fibrosis.
The researchers hypothesize that these communication networks between cells change as the disease progresses, so some drugs might be more effective earlier and others at later stages. And the same drug might not work for all stages of the disease. Currently, the team is working to optimize NTRK3 inhibitors for the treatment of liver fibrosis.
Next, all candidates will be screened using a cell culture system and then tested in preclinical models of liver disease, with the hope of development of new effective treatments to block hepatic steatosis.