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Cited by 39Liver Disease Diagnosis and TreatmentLiver physiology and pathologyHepatocellular Carcinoma Treatment and Prognosis

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC

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Boslem, Ebru, Reibe, Saskia, Carlessi, Rodrigo, Smeuninx, Benoit, Tegegne, Surafel, Egan, Casey L., McLennan, Emma, Terry, Lauren V. +15 more·2023·Science Advances
DOI 10.1126/sciadv.adh0831PMC PMC10499313
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Abstract

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.

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  • In a mouse model mimicking human NASH-driven HCC, treatment with olamkicept significantly regresses NASH and markedly reduces NASH-driven HCC.

    “In addition, in a mouse model that mimics human NASH-driven HCC, treatment of olamkicept can significantly regress NASH and markedly reduce NASH-driven HCC [98].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [98]

    The Introduction identifies the HFD-fed MUP-uPA mouse as a model of human NASH-to-HCC progression. But the Results section on monotherapies reports only mild benefits from sgp130Fc (olamkicept): it improved tumor incidence but did not reduce tumor number or volume. The reported NASH regression and marked HCC reduction came from combining sgp130Fc with BGP-15, not from olamkicept alone. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Authors
Boslem, E., Reibe, S., Carlessi, R., Smeuninx, B., Tegegne, S., Egan, C. L., McLennan, E., Terry, L. V., Nobis, M., Mu, A., Nowell, C., Horadagoda, N., Henstridge, D. C., Mellett, N. A., Timpson, P., Jones, M., Denisenko, E., Forrest, A. R. R., Tirnitz-Parker, J. E. E., Meikle, P. J., Rose-John, S., Karin, M., & Febbraio, M. A.
Affiliations
  • Monash University (AU)
  • Garvan Institute of Medical Research (AU)
  • The University of Western Australia (AU)
  • European Bioinformatics Institute (GB)
  • The University of Sydney (AU)
  • Baker Heart and Diabetes Institute (AU)
  • Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.
  • Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
  • University of California San Diego (US)
Corresponding author
  • Boslem, Ebru
  • Reibe, Saskia
  • Carlessi, Rodrigo
  • Smeuninx, Benoit
  • Febbraio, Mark A.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-09-15
Volume
9
Issue
37
Pages
eadh0831-eadh0831
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adh0831
PMC
PMC10499313
OpenAlex
W4386706487
Cited by
39
References
14
Citations by year
2026: 15 · 2025: 10 · 2024: 13 · 2023: 1
FWCI
8.15
Type
journal article
Language
en
Update notices
correction (2023-11-17)
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, cc-by-nc)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by-nc)
  • Figshare (submittedVersion, cc-by-nc)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • National Institutes of Health
  • National Health and Medical Research Council (1122227, 1042465, 1041760)
  • National Cancer Institute (R01CA234128, R01CA198103, R01CA211794)
  • National Institute of Allergy and Infectious Diseases (R37AI043477)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120714)
  • National Institute of Environmental Health Sciences (P42ES010337)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
nonalcoholic steatohepatitis, hepatocellular carcinoma, endoplasmic reticulum stress, inflammation, BGP-15, high-fat diet, obesity, single-nucleus RNA sequencing, hepatocyte heterogeneity, combination therapy
MeSH terms
Animals, Carcinoma, Hepatocellular, Humans, Inflammation, Liver Neoplasms, Hepatocytes, Mice, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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