Therapeutic blockade of ER-Stress and inflammation prevents NASH and progression to HCC

Abstract: The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely due to
increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor.
There are no approved treatments to treat NASH. Here, we first employed single nucleus RNA
sequencing to characterize a mouse model that mimics human NASH driven HCC, the MUPuPA
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.

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This record contains data and code related to Figure 1 and Supplementary Figure 1 (snRNA-seq analysis).

This record contains code related to Supplementary Figure 7 and Supplementary Figure 9 (bulk RNA-seq analysis).