Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC
Version 2 2024-11-04, 05:21Version 2 2024-11-04, 05:21
Version 1 2023-12-06, 01:48Version 1 2023-12-06, 01:48
journal contribution
posted on 2023-12-06, 01:48authored byEbru 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.