Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt de BGP-15 (un inhibiteur du stress du réticulum endoplasmique) et de gp130Fc (un inhibiteur du processus inflammatoire) pour prévenir la progression d'une stéatose hépatique non alcoolique vers un carcinome hépatocellulaire
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. Clinically safe drugs that target cellular stress and inflammation could successfully treat NASH and liver cancer.