Hic-5 Antisense Oligonucleotide Inhibits Advanced Hepatic Fibrosis and Steatosis

Overview

Journal JHEP Rep

Specialty Gastroenterology

Date 2024 Oct 24

PMID 39444410

Authors

Masahito Noguchi

Aya Miyauchi

Yoshiaki Masaki

Masashi Sakaki

Xiao-Feng Lei

Momoko Kobayashi-Tanabe

Akira Miyazaki

Takeshi Aoki

Hitoshi Yoshida

Kohji Seio

Joo-Ri Kim-Kaneyama

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health burden. Progressive liver fibrosis can lead to severe outcomes; however, there is a lack of effective therapies targeting advanced fibrosis. Hydrogen peroxide-inducible clone-5 (Hic-5), an adaptor protein in focal adhesion, is critical for promoting liver fibrosis in hepatic stellate cells. This study investigated its clinical applicability by examining hepatic Hic-5 expression in human fibrotic tissues, exploring its association with MASH, and assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting Hic-5 in a MASH mouse model.

Methods: Hepatic Hic-5 expression in human fibrotic tissues underwent pathological image analysis and single-cell RNA sequencing. ASOs targeting Hic-5 were developed and tested using cell models. An MASH mouse model was used to evaluate the effects of anti- ASOs on advanced fibrosis and steatosis.

Results: Hepatic Hic-5 expression increased with the progression of fibrosis, particularly in advanced stages. Single-cell RNA sequencing revealed Hic-5 expression primarily in hepatic stellate cells. In MASH-associated fibrosis, Hic-5 expression correlated with the expression of fibrotic genes. In the MASH mouse model, hepatic Hic-5 expression increased with disease progression. Anti- ASOs effectively suppressed Hic-5 expression and attenuated advanced fibrosis and steatosis , indicating their therapeutic potential.

Conclusions: Hepatic Hic-5 expression is associated with advanced liver fibrosis and MASH. Anti- ASOs are promising therapeutic interventions for MASH accompanied by advanced fibrosis. These findings provide valuable insights into potential clinical treatments for advanced liver fibrosis.

Impact And Implications: This study investigated the role of Hic-5 in liver fibrosis and steatohepatitis, highlighting its potential as a therapeutic target. We developed an antisense oligonucleotide (ASO) that was particularly transportable to the liver, and targeted Hic-5. Anti- ASO exhibited therapeutic efficacy for liver fibrosis and steatosis , indicating its therapeutic potential for liver fibrosis and steatosis. ASOs have already achieved dramatic therapeutic effects as approved nucleic acid drugs. Thus, anti- ASO is expected to lead the direct generation of seed compounds for the clinical development of drugs for liver fibrosis and steatosis.

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