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

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; Natalie A. Mellett; Paul Timpson; Matthew Jones; Elena Denisenko; Alistair R.R. Forrest; Janina E.E. Tirnitz-Parker; Peter J. Meikle; Stefan Rose-John; Michael Karin; Mark A. Febbraio

doi:10.1126/sciadv.adh0831

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

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, Natalie A. Mellett, Paul Timpson, Matthew Jones, Elena Denisenko, Alistair R.R. Forrest, Janina E.E. Tirnitz-Parker, Peter J. Meikle, Stefan Rose-JohnMichael Karin, Mark A. Febbraio

Drug Discovery Biology

Research output: Contribution to journal › Article › Research › peer-review

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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.

Original language	English
Article number	eadh0831
Number of pages	17
Journal	Science Advances
Volume	9
Issue number	37
DOIs	https://doi.org/10.1126/sciadv.adh0831
Publication status	Published - 15 Sept 2023

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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., Mellett, N. A., Timpson, P., Jones, M., Denisenko, E., Forrest, A. R. R., Tirnitz-Parker, J. E. E., Meikle, P. J., ... Febbraio, M. A. (2023). Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. Science Advances, 9(37), Article eadh0831. https://doi.org/10.1126/sciadv.adh0831

@article{ce73c179c2ae4c9aa16e736a7816df9d,

title = "Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC",

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.",

author = "Ebru Boslem and Saskia Reibe and Rodrigo Carlessi and Benoit Smeuninx and Surafel Tegegne and Egan, \{Casey L.\} and Emma McLennan and Terry, \{Lauren V.\} and Max Nobis and Andre Mu and Cameron Nowell and Neil Horadagoda and Mellett, \{Natalie A.\} and Paul Timpson and Matthew Jones and Elena Denisenko and Forrest, \{Alistair R.R.\} and Tirnitz-Parker, \{Janina E.E.\} and Meikle, \{Peter J.\} and Stefan Rose-John and Michael Karin and Febbraio, \{Mark A.\}",

year = "2023",

month = sep,

day = "15",

doi = "10.1126/sciadv.adh0831",

language = "English",

volume = "9",

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Boslem, E, Reibe, S, Carlessi, R, Smeuninx, B , Tegegne, S, Egan, CL, McLennan, E, Terry, LV, Nobis, M, Mu, A , Nowell, C, Horadagoda, N, Mellett, NA, Timpson, P, Jones, M, Denisenko, E, Forrest, ARR, Tirnitz-Parker, JEE, Meikle, PJ, Rose-John, S, Karin, M & Febbraio, MA 2023, 'Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC', Science Advances, vol. 9, no. 37, eadh0831. https://doi.org/10.1126/sciadv.adh0831

TY - JOUR

T1 - Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC

AU - Boslem, Ebru

AU - Reibe, Saskia

AU - Carlessi, Rodrigo

AU - Smeuninx, Benoit

AU - Tegegne, Surafel

AU - Egan, Casey L.

AU - McLennan, Emma

AU - Terry, Lauren V.

AU - Nobis, Max

AU - Mu, Andre

AU - Nowell, Cameron

AU - Horadagoda, Neil

AU - Mellett, Natalie A.

AU - Timpson, Paul

AU - Jones, Matthew

AU - Denisenko, Elena

AU - Forrest, Alistair R.R.

AU - Tirnitz-Parker, Janina E.E.

AU - Meikle, Peter J.

AU - Rose-John, Stefan

AU - Karin, Michael

AU - Febbraio, Mark A.

PY - 2023/9/15

Y1 - 2023/9/15

N2 - 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.

AB - 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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DO - 10.1126/sciadv.adh0831

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AN - SCOPUS:85171232102

SN - 2375-2548

VL - 9

JO - Science Advances

JF - Science Advances

IS - 37

M1 - eadh0831

ER -

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

Abstract

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