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Researchers Find Stress Effector ATF4 May Suppress Hepatocarcinogenesis

By: Sarah Lynch
Posted: Friday, May 26, 2023

A team of researchers at the University of California San Diego (UCSD) School of Medicine studied activating transcription factor 4 (ATF4), a key mediator of the liver stress response. Contrary to previous theories, they found that ATF4 was protective of the liver against hepatocyte death and further tumor formation. In addition, ATF4 seemed to promote the expression of the protein SLC7A11, which helped to suppress ferroptosis. These research findings were published in the Journal of Hepatology.

“Our study suggests that ferroptosis may be the most relevant form of hepatocyte death that leads to inflammation, compensatory proliferation, and cancer in the liver,” stated Michael Karin, PhD, in a UCSD press release.

The study authors further explained: “ATF4 is a key downstream effector of the [endoplasmic reticulum] and integrated stress responses, which are triggered by nutrient deprivation, viral infection, and oxidative stress. However, under persistent stress or when adaptation is insufficient, ATF4 promotes cell death. Of note, liver-specific ATF4 ablation inhibits hepatosteatosis, which could be a protective response that prevents further progression to steatohepatitis. Indeed, loss of ATF4 enhances liver damage.”

The researchers exposed groups of mice to various stressors to simulate the stress of liver cancer. They separated the mice into four groups. Hepatocyte-specific ATF4-deficient MUP-uPA mice and control MUP-uPA/Atf4F/F mice were fed high-fat diets to induce nonalcoholic steatohepatitis. Atf4F/F and Atf4∆hep mice were injected with diethylnitrosamine to model carcinogen-induced hepatocellular carcinoma. Various sequencing analyses were performed to identify and define the role of ATF4-induced SLC7A11 expression in hepatocarcinogenesis.

Hepatocyte ATF4 ablation inhibited hepatosteatosis but increased susceptibility to iron-dependent ferroptosis, which accelerated the development of hepatocellular carcinoma. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 was shown to have a protective function in normal hepatocytes, despite being upregulated in established hepatocellular carcinoma sites. By maintaining the production of glutathione, ATF4 inhibited ferroptosis-dependent cell death.

Disclosure: For full disclosures of the study authors, visit

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