Therapeutic Blockade of ER Stress and Inflammation Prevents NASH and Progression to HCC

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Sep 13

PMID 37703359

Authors

Ebru Boslem

Saskia Reibe

Rodrigo Carlessi

Benoit Smeuninx

Surafel Tegegne

Casey L Egan

Emma McLennan

Lauren V Terry

Max Nobis

Andre Mu

Cameron Nowell

Neil Horadagoda

Darren C Henstridge

Natalie A Mellett

Paul Timpson

Matthew Jones

Elena Denisenko

Alistair R R Forrest

Janina E E Tirnitz-Parker

Peter J Meikle

Stefan Rose-John

Michael Karin

Mark A Febbraio

Affiliations

Soon will be listed here.

Abstract

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.

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