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Relieving ER stress to target NASH-driven hepatocellular carcinoma

An Author Correction to this article was published on 05 January 2019

This article has been updated

A key component in the development from fatty liver to hepatocellular carcinoma (HCC) is the appearance of nonalcoholic steatohepatitis (NASH). The precise cellular processes that trigger the advancement of NASH towards HCC are not well understood. In 2018, three key papers were published that help us better understand these processes.

Key advances

  • Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) that is driven by nonalcoholic steatohepatitis (NASH)5,6,7.

  • Caspase 2, a non-apoptotic caspase, is activated by the IRE1α branch of ER stress and controls NASH by cleaving site-1 protease, which activates sterol regulatory element-binding proteins and results in NASH development5.

  • Inhibiting Bax inhibitor 1 increases the activity of the IRE1α signalling branch of the ER stress response and results in NASH, but more importantly the phenotype can be reversed by treating Bax inhibitor 1 null mice with an IRE1α RNase activity inhibitor7.

  • Another approach to treat NASH-driven HCC is the use of small molecules mimicking AMPK-mediated acetyl-CoA carboxylase (ACC) inhibition as ACC-activating mutations increase hepatic carcinogenesis6.

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Fig. 1: The spectrum of disease progression from a healthy liver to hepatocellular carcinoma due to lipid overload.

Change history

  • 05 January 2019

    In the original version of this manuscript, the incorrect names for two proteins were given. S1P and S2P should have been defined as site-1 protease and site-2 protease. This has been corrected in the HTML and PDF versions of the manuscript.


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Correspondence to Mark A. Febbraio.

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Reibe, S., Febbraio, M.A. Relieving ER stress to target NASH-driven hepatocellular carcinoma. Nat Rev Endocrinol 15, 73–74 (2019).

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