Using single-nuclear sequencing of mice and human liver tissue and advanced 3D glass imaging of mice to characterize key scar-producing liver cells—researchers at the Icahn School of Medicine at Mount Sinai have uncovered novel candidate drug targets for non-alcoholic fatty liver disease (NAFLD).

The findings, “An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in non-alcoholic steatohepatitis,” were published in Science Translational Medicine, and may lead to new treatments.

“Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies,” wrote the researchers. “To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model.”

The researchers performed single-nuclear sequencing in parallel studies of both mouse models of NASH and human liver tissue from nine subjects with NASH and two controls. They identified a shared number of 68 pairs of potential drug targets across the two species.

“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 key scar-producing cells in the liver,” said senior study author Scott L. Friedman, MD, the Irene and Arthur M. Fishberg professor of medicine, dean for therapeutic discovery, and chief of liver diseases at Icahn Mount Sinai. “In combining this new glass liver imaging approach—an advanced tissue clearing method that enables deep insight—along with gene expression analysis in individual stellate cells, we have unveiled an entirely new understanding of how these cells generate scarring as NASH advances to late stages.”

“We confirmed the importance of one such pair of proteins, 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 fight NASH fibrosis,” said first author Shuang (Sammi) Wang, PhD, an instructor in the division of liver diseases. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of signals that accelerate scarring, which represent a previously unrecognized set of drug targets.”

The researchers are currently working with Icahn Mount Sinai chemists to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. They hope to extend their efforts to determine if similar interactions among fibrogenic cells underlie fibrosis of other tissues including the heart, lung, and kidneys.

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