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Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC
journal contributionposted 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.
Publication titleScience Advances
PublisherAmerican Association for the Advancement of Science (AAAS)
Place of publicationUnited States
Event VenueMonash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
32 Biomedical and Clinical Sciences3211 Oncology and CarcinogenesisRare DiseasesDigestive DiseasesHepatitisObesityLiver DiseaseLiver CancerBiotechnologyCancer2 Aetiology5.1 Pharmaceuticals5 Development of treatments and therapeutic interventions2.1 Biological and endogenous factorsHumansAnimalsMiceCarcinoma, HepatocellularNon-alcoholic Fatty Liver DiseaseLiver NeoplasmsHepatocytesInflammation