A recent study from Adelaide University, published in Science Advances, indicates that blocking the cellular enzyme Caspase-2, previously considered to offer protection against fatty liver disease, may instead increase the risk of chronic liver damage and cancer in aging organisms. The research suggests that the absence of Caspase-2 promotes abnormal growth in liver cells, contributing to inflammation, fibrosis, and an elevated risk of liver cancer.
Research Findings on Caspase-2
The study challenges earlier assumptions regarding the universal benefits of inhibiting Caspase-2. Dr. Loretta Dorstyn, lead researcher from the Centre for Cancer Biology, stated that Caspase-2 is crucial for maintaining genetic stability and regulating fat levels within liver cells. Liver cells commonly possess extra genetic material, known as polyploidy, which can aid in managing stress. However, the study demonstrated that abnormally high levels of polyploidy without functional Caspase-2 can lead to cellular damage.
Experimental Observations
Researchers utilized genetically modified mouse models lacking functional Caspase-2. Observations included unusually large liver cells exhibiting significant genetic and cellular damage. Over time, these mice developed chronic liver inflammation and characteristics similar to hepatitis-like liver disease, such as scarring, oxidative damage, and inflammation-associated cell death. As these animals aged, they showed a higher likelihood of developing liver cancer, with spontaneous liver tumors occurring at rates up to four times higher than in control mice, consistent with hepatocellular carcinoma.
Dr. Dorstyn clarified that while short-term inhibition of Caspase-2 might offer protection in young subjects or aid in preventing fatty liver disease, the study suggests that its long-term absence is detrimental. Caspase-2 plays a role in removing damaged and abnormal liver cells during the aging process. Without this enzyme, these cells can accumulate, potentially becoming cancerous and fostering an environment conducive to liver cancer.
Implications for Drug Development and Liver Health
Professor Sharad Kumar, senior author of the study, highlighted the implications for drug development. He noted prior interest in targeting Caspase-2 to address metabolic liver disease and reduce liver cancer risk. However, the research indicates that such an approach could lead to unforeseen consequences later in life, potentially increasing susceptibility to chronic liver inflammation, fibrosis, and cancer.
Liver disease remains a growing global health concern, influenced by factors such as aging populations, obesity, and metabolic disorders. Liver cancer is ranked as the 6th most common cancer worldwide. In 2022, liver cancer was responsible for approximately 760,000 deaths globally, according to the World Cancer Research Fund.