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.
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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The authors declare no competing interests.
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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). https://doi.org/10.1038/s41574-018-0145-7