Researchers discover new candidate drug targets for advanced non-alcoholic fatty liver disease

Using the latest technologies, including both single-nucleus sequencing of mice and human liver tissue, and advanced 3D imaging of mice in glass to characterize major scar-producing liver cells, researchers have discovered new candidate drug targets for non-alcoholic fatty liver disease (NAFLD). The research was conducted by researchers at the Icahn School of Medicine at Mount Sinai.

Using these innovative methods, researchers have uncovered a cell-to-cell communication network that drives scarring as liver disease progresses. The results, published online January 4 in Science Translational Medicinecould lead to new treatments.

Characterized by fatty liver and often associated with type 2 diabetes, hypertension and elevated blood lipids, NAFLD is a worldwide threat. In the United States, an estimated 30 to 40 percent of adults are affected, with about 20 percent of these patients having a more advanced stage called nonalcoholic steatohepatitis, or NASH, which is characterized by inflammation of the liver and can progress in advanced wound healing (cirrhosis) and liver failure.

NASH is also the fastest growing cause of liver cancer worldwide. Because advanced stages of NASH are caused by the buildup of fibrosis or scarring, attempts to block fibrosis are at the heart of efforts to treat NASH, but currently no drugs are approved for this purpose, say the investigators.

As part of the experiments, the researchers performed single-nucleus sequencing in parallel studies of both mouse models of NASH and human liver tissue of nine subjects with NASH and two controls. They identified a shared number of 68 pairs of potential drug targets between the two species. Additionally, the researchers pursued one such pair by testing an existing cancer drug in mice as a proof of concept.

We aimed to understand the basis of this fibrotic scarring and identify drug targets that could lead to new treatments for advanced NASH by studying hepatic stellate cells, which are the major scar-producing cells in the liver. By combining this new glass liver imaging approach – an advanced tissue cleansing method that allows for deep insight – together with gene expression analysis in individual stellate cells, we have unveiled an entirely new understanding of how these cells generate human scars. as NASH advances to the advanced stages.”


Scott L. Friedman, MD, Ssenior study author, Irene and Dr. Arthur M. Fishberg Professor of Medicine, Dean for Therapeutic Discovery and Chief of Liver Diseases at Icahn Mount Sinai

The researchers found that in advanced disease, stellate cells develop a dense network, or web, of interactions with each other that facilitate these 68 pairs of unique interactions not previously identified in this disease.

“We confirmed the importance of one of these protein pairs, NTF3-NTRK3, using a molecule already developed to block NTRK3 in human cancers and repurposed it to establish its potential as a new drug to combat NASH fibrosis,” he said. said first author Shuang (Sammi ) Wang, PhD, an instructor at the Division of Liver Disease. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of signals that accelerate scarring, representing a previously unrecognized array of drug targets.”

Researchers speculate that the circuitry of how cells communicate with each other evolves as the disease progresses, so some drugs may be more effective earlier and others at later stages. And the same drug may not work for all stages of the disease.

The researchers are currently working with Icahn Mount Sinai chemists to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. Next, the researchers plan to functionally screen all interacting candidates in a cell culture system, followed by testing in preclinical models of liver disease, as they did for NTRK3. Additionally, they hope to extend their efforts to determine whether similar interactions between fibrogenic cells underlie fibrosis of other tissues including the heart, lungs and kidneys.

The paper is titled “An autocrine signaling loop in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis.”

Source:

The Mount Sinai Hospital / Mount Sinai School of Medicine

Magazine reference:

Wang, S. et al. (2023) An autocrine signaling loop in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine. doi.org/10.1126/scitranslmed.add3949.

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