Researchers at the University of Adelaide have found that blocking the enzyme Caspase-2, previously seen as a potential treatment for fatty liver disease, may increase the risk of chronic liver damage and cancer over time. In genetically modified mice lacking functional Caspase-2, liver cells grew abnormally large and accumulated genetic damage, leading to inflammation, scarring, and tumors. The findings, published in Science Advances, challenge the development of Caspase-2 inhibitors.
A new study from the University of Adelaide reveals potential long-term risks associated with inhibiting the enzyme Caspase-2, which has been considered for treating fatty liver disease. Published in Science Advances under the title 'Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice,' the research used genetically modified mice lacking Caspase-2 or carrying a nonfunctional version. These mice developed unusually large liver cells with significant genetic and cellular damage, resulting in chronic inflammation, scarring, oxidative damage, and hepatitis-like conditions. As the animals aged, they showed a much higher incidence of liver tumors—up to four times more than normal mice—consistent with hepatocellular carcinoma. Liver cancer caused nearly 760,000 deaths worldwide in 2022, ranking as the sixth most common cancer, according to the World Cancer Research Fund. Lead researcher Dr. Loretta Dorstyn from the Centre for Cancer Biology explained, 'Liver cells normally have extra copies of genetic material—known as polyploidy—and while this feature can help the liver cope with stress, our study shows that without the enzyme Caspase-2, abnormally high levels of polyploidy in the liver can be damaging.' She added, 'Our study demonstrates that Caspase-2 is essential for removing damaged and abnormal liver cells as we age. Without it, these cells accumulate, and can become cancerous, while also creating an environment that predisposes the liver to cancer.' Senior author Professor Sharad Kumar cautioned, 'There has been significant interest in targeting Caspase-2 to treat metabolic liver disease and reduce liver cancer risk. Our data shows that this approach could have serious unintended consequences later in life, increasing susceptibility to chronic liver inflammation, fibrosis and cancer.' Dr. Dorstyn noted short-term benefits in young animals but emphasized long-term detriment. The results urge caution in developing Caspase-2 inhibitors amid rising global liver disease driven by obesity and aging populations.
