Changing the Narrative

Hepatocellular carcinoma (HCC) – the sixth most common cancer type worldwide – is closely associated with environmental and metabolic stressors, such as obesity, type II diabetes (T2D), toxicant exposure, and viral hepatitis. These factors can trigger endoplasmic reticulum stress, and subsequent hepatocyte death – leading to non alcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH).

“The prevalence of global obesity and T2D has attained the status of a global pandemic,” says Feng He, lead author of a study conducted by the Shanghai University of Traditional Chinese Medicine and UC San Diego School of Medicine that has investigated the role of activating transcription factor 4 (ATF4) – a protein historically associated with cancer cell growth (1). But, while investigating the function of ATF4 in NAFLD progression, the team were surprised to discover that it protected the liver against hepatocyte death and tumor formation – making it a potential clinical target for preventing HCC development.

In the study, ATF4 deficient MUP-uPA mice and control mice were fed a high-fat diet to promote NASH-induced HCC. Researchers found that the ATF4 deficient mice had livers littered with surface nodules, increased hepatocyte damage, and necroinflammatory injury – ultimately resulting in advanced liver cancer. Most importantly, they discovered that ATF4 was key in activating SLC7A11 expression – a protein involved in maintaining hepatocyte homeostasis and suppressing ferroptosis, an iron-dependent cell death. In short, ATF4 deficiency enhances the chance of stress-induced ferroptosis and liver tumor formation. The researchers also concluded that the amounts of ATF4 and SLC7A11 were positively correlated in human HCC and livers of NASH patients.

“Developing accurate cancer models to truly mimic human cancer characteristics is always a challenge,” says He. However, the research successfully opened new avenues for cancer prevention, and in the future, He aims to not only explore the potential of ferroptosis inhibitors, but also hopes to “uncover the threshold of ATF4 in its function from a cancer protector to a cancer promoter and develop small ATF4 modulators that could be optimized for cancer prevention and cancer treatment.”