Liver cancer is the third leading cause of cancer death and the sixth most common cancer type worldwide. Major risk factors include environmental and metabolic stressors, such as obesity, viral hepatitis, toxicant exposure, and steatohepatitis (fatty and inflamed liver). Such stressors damage the liver by killing hepatocytes, the major cell type in the liver. The liver cell death then triggers an inflammatory response which signals the liver to generate a new batch of hepatocytes. But this sudden push towards cellular proliferation also increases the risk of tumor formation.
In a new study, scientists at Shanghai University of Traditional Chinese Medicine (SHUTCM) investigated the role of activating transcription factor 4 (ATF4), a key mediator of the liver stress response. Despite being previously associated with advanced liver cancer, the researchers found that ATF4 actually protected the liver against hepatocyte death and subsequent tumor formation. ATF4 signaling is part of the organism’s specialized conserved stress response mechanisms to adapt to environmental stressors. The unexpected results could now inspire new clinical strategies for preventing liver disease and cancer.
The study, published on March 28, 2023 in the Journal of Hepatology, was led by senior scientists Feng He, PhD, investigator of Academy of integrative medicine at SHUTCM, Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine, and Benjamin C. Yaden, PhD, associate vice president of Diabetes Novel Therapies and External Innovation at Eli Lilly.
ATF4 is the key downstream regulator of ER stress and integrated stress signaling. Its levels are typically low in healthy cells but are elevated when the cell experiences stress. In response to ER stress or metabolic stress, ATF4 is upregulated to orchestrate the special stress response program to dictate the cell survival and adaptation to the stress or the ultimate cell death if the stress is severe or lasted too long. To uncover the role of ATF4 in the progression of liver cancer, researchers developed mouse models of liver inflammation and liver cancer with ATF4-deficient hepatocytes. The researchers were surprised to find that ATF4-deficient mice showed more hepatocyte cell death, inflammation, compensatory cellular proliferation and accelerated liver cancer development. This suggested that ATF4 protected against liver cancer in some way.
Further experiments led by Feng He’s group at SHUTCM, in collaboration with groups of Michael Karin and Benjamin C. Yaden, confirmed that upon induction, ATF4 promoted the expression of SLC7A11, a protein that helps maintain hepatocyte and tissue homeostasis. SLC7A11 then helped suppress a specific type of cell death, called ferroptosis. By reducing the amount of ferroptosis, the ATF4-SLC7A11 axis protected hepatocytes and slowed the progression from liver damage to liver cancer.
The study flips the script on liver cancer and may hold the key to liver cancer prevention and therapy, providing a basis for exerting the superior mechanism of stress response and homeostasis of traditional Chinese medicine in the prevention and treatment of hepatitis and liver cancer. The researchers believe ferroptosis inhibitors or ATF4 activators may be clinically useful in preventing steatohepatitis and its progression to cancer.
The study was funded, in part, by the National Natural Science Foundation of China (grant 82172947).
DOI: 10.1016/j.jhep.2023.03.016
