Post-transcriptional regulation by RNA binding proteins in liver fibrosis

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Sanford Burnham Prebys Medical Discovery Institute $910,940 on August 10, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate post-transcriptional regulation of liver fibrosis by RNA binding proteins.

The recipient will conduct basic research to identify and characterize RNA binding proteins (RBPs) that control fibrosis-related gene expression in liver cells, with specific focus on LARP6, which is highly active in activated hepatic stellate cells and promotes collagen production. The work includes three main research components: identifying additional RBPs influencing fibrosis; investigating molecular mechanisms through which LARP6 interacts with RNA and other proteins to promote fibrogenesis; and exploring therapeutic approaches to block LARP6 activity using genetic mouse models with cell-type-specific LARP6 deletion in hepatic stellate cells, antisense oligonucleotides to deplete LARP6, and small molecule compounds that inhibit LARP6 function. The research addresses metabolic dysfunction-associated steatotic liver disease and metabolic alcoholic liver disease, major causes of liver fibrosis that can progress to cirrhosis, liver failure, and cancer.

Performance occurs in La Jolla, California. The award period runs through April 30, 2030.

Abstract

Chronic liver injury can lead to fibrosis, a condition where scar tissue builds up in the liver, disrupting its normal structure and function, which can progress to cirrhosis, liver failure, and cancer. Metabolic dysfunction- associated steatotic liver disease (MASLD) and metabolic alcoholic liver disease (METALD) are major causes of liver fibrosis. Fibrosis represents a critical window for therapeutic intervention before permanent damage occurs. Fibrosis is driven by the activation of hepatic stellate cells (HSCS), which produce scar-forming proteins in response to liver injury and inflammation. Although the external triggers of this process are well understood, the internal mechanisms within HSCS that control fibrosis are less clear. Recent research has highlighted the role of RNA binding proteins (RBPS) in regulating fibrosis-related genes in various organs. We discovered that the RBP LARP6 is highly active in activated HSCS, where IT promotes the production of collagen, a key component of scar tissue. Reducing LARP6 levels in cell culture models significantly decreased fibrosis markers, suggesting IT plays a central role in the disease. This proposal aims to better understand how LARP6 and other RBPS contribute to liver fibrosis. We identify additional RBPS that influence fibrosis and study how they control gene expression in liver cells. Second, we investigate how LARP6 interacts with RNA and other proteins on the molecular level to promote fibrogenesis. Finally, we begin explore the safety and efficacy potential of new therapeutic approaches to block LARP6 activity, including the use of a genetic mouse models with cell-type specific LARP6 deletion in HSCS, antisense oligonucleotides (ASOS) that deplete LARP6, and small molecule compounds that inhibit LARP6 function. Our work will provide new insights into the molecular drivers of liver fibrosis that could lead to innovative treatments for this widespread and serious condition.