Article
作者: Boslem, Ebru ; Horadagoda, Neil ; McLennan, Emma ; Meikle, Peter J ; Rose-John, Stefan ; Nobis, Max ; Henstridge, Darren C ; Jones, Matthew ; Tegegne, Surafel ; Mu, Andre ; Forrest, Alistair R R ; Terry, Lauren V ; Nowell, Cameron ; Denisenko, Elena ; Egan, Casey L ; Smeuninx, Benoit ; Carlessi, Rodrigo ; Karin, Michael ; Tirnitz-Parker, Janina E E ; Febbraio, Mark A ; Timpson, Paul ; Mellett, Natalie A ; Reibe, Saskia
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.