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Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC

journal contribution
posted on 2023-12-06, 01:48 authored by 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 HenstridgeDarren Henstridge, Natalie A Mellett, Paul Timpson, Matthew Jones, Elena Denisenko, Alistair RR Forrest, Janina EE Tirnitz-Parker, Peter J Meikle, Stefan Rose-John, Michael Karin, Mark A Febbraio
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 MUP-uPA 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 MUP-uPA 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.

History

Sub-type

  • Article

Publication title

Science Advances

Medium

Print-Electronic

Volume

9

Issue

37

Pagination

eadh0831

eISSN

2375-2548

ISSN

2375-2548

Publisher

American Association for the Advancement of Science (AAAS)

Publication status

  • Published

Place of publication

United States

Event Venue

Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.