Researchers participating in the IDIBELL study | Thursday, September 1, 2022 Liver cancer is the sixth most common in the world and the third with the worst prognosis. According to the World Health Organization (WHO), in 2020 a total of 830,000 deaths were attributed to it; a figure in constant growth that is only surpassed by those that are recognized for lung cancer and colon cancer. There are several risk factors for this type of tumor, such as excessive alcohol consumption, obesity, sedentary lifestyle, viral infections caused by hepatitis B and C, and drug use, among others. It should be noted that in terms of incidence and mortality, the figures are higher in men than in women. Although great progress has been made in recent years, progress is still needed in understanding the molecular mechanisms of this disease and in the design of new therapeutic options. Now, a study published in the journal Hepatology highlights the importance of a protein called NOX4 in the development of hepatocellular carcinoma, which is the most aggressive and, unfortunately, the most common form of liver cancer. Using genetically modified mice, cell cultures and human tumor samples, Isabel Fabregat’s team, head of the TGF-beta and Cancer group at the Bellvitge Biomedical Research Institute (IDIBELL), has managed to identify the molecular mechanisms regulated by this protein and has deciphered its protective role against cancer. “Although liver cancer cells are especially avid for glucose and lipids, which allows them to multiply rapidly, NOX4 slows down these processes,” explains Fabregat, who is also a professor at the University of Barcelona and head of the CIBER group in the area of Liver and Digestive Diseases (CIBEREHD). She adds: “When NOX4 activity is low, cellular metabolism is reprogrammed and oxidative stress is caused, which favors the tumor to proliferate more and increase its ability to invade other tissues. Consequently, the levels of NOX4 can determine the evolution of liver cancer”. Differences between NOX proteins During the onset of liver cancer, an oxidative microenvironment is created that causes cellular stress, which activates NOX proteins. However, not all proteins in the family have the same functions. While NOX4 has a protective effect, as this study has revealed, NOX1 contributes to cancer progression. “The results indicate that NOX1 favors an increase in oxidative stress, a process that NOX4 manages to reduce”, explains Irene Peñuelas, postdoctoral researcher at IDIBELL, as well as at CIBEREHD and first signatory of the study. The NOX proteins would be achieving these changes through the regulation of the transcription factors MYC and NRF2, responsible for the expression of many genes involved in cancer. “We have seen that in the absence of NOX4, the expression of NOX1 or NOX2 is increased, which causes an increase in the activity of NRF2 and MYC, which are responsible for changes in the mitochondria and a reprogramming of the oxidative metabolism, increasing the energy capacity of the cell”, says Peñuelas. In fact, previous studies by the same group had indicated that the elimination of NOX4 stimulates the proliferation of liver cells. “Therapeutic applications of NOX4 are very broad. We may be interested in inhibiting it to promote liver regeneration in situations of chronic diseases that produce liver fibrosis, or just the opposite, compensating for its lack of activity in cases of cancer to slow down progression”, concludes Fabregat. The work has been carried out in the context of the CIBER consortium belonging to the Carlos III Health Institute and has been led by IDIBELL with the participation of professionals from the Catalan Institute of Oncology, the Bellivtge University Hospital and the University of Barcelona in collaboration with groups of research at a national level with CIC bioGUNE, the Severo Ochoa Molecular Biology Center, the Autonomous University of Madrid, IRB Barcelona, and internationally with scientists from University College Dublin. Article reference: Hepatology. The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing hepatocellular carcinoma progression https://doi.org/10.1002/hep.32702