Scientists at Adelaide University have found that blocking the enzyme Caspase-2, previously considered a potential target for treating fatty liver disease, may increase the risk of chronic liver damage and cancer as individuals age. The research, published in Science Advances, shows that loss of Caspase-2 leads to abnormal liver cell growth, inflammation, fibrosis, and a higher incidence of liver cancer.
The study used genetically modified mouse models to observe the effects of Caspase-2 deficiency. Mice lacking this enzyme developed enlarged liver cells with significant genetic and cellular damage. Over time, these mice showed signs of chronic inflammation and hepatitis-like disease such as scarring and oxidative damage. They also had a much greater likelihood of developing spontaneous liver tumors as they aged.
"Over time, these mice developed chronic liver inflammation and characteristics of hepatitis-like liver disease including, scarring, oxidative damage and a type of cell death linked to inflammation. As the animals aged, they were much more likely to develop liver cancer," said Dr Loretta Dorstyn from the Centre for Cancer Biology.
The research found that older mice without functional Caspase-2 had up to four times the rate of liver cancer compared to normal mice. This form of cancer was consistent with hepatocellular carcinoma.
Dr Dorstyn noted that the findings challenge previous beliefs about inhibiting Caspase-2: "While inhibiting this enzyme can be protective in young animals or may help prevent fatty liver disease in the short term, our study shows that its long-term loss is clearly detrimental.
"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 emphasized the implications for drug development: "There has been significant interest in targeting Caspase-2 to treat metabolic liver disease and reduce liver cancer risk," Prof Kumar said.
"Our data shows that this approach could have serious unintended consequences later in life, increasing susceptibility to chronic liver inflammation, fibrosis and cancer."
Liver disease continues to pose a major health challenge worldwide due to factors such as aging populations and rising rates of obesity and metabolic disorders. In 2022 alone, nearly 760,000 deaths were attributed to liver cancer globally according to data from the World Cancer Research Fund.
