REVEALED: HIDDEN CANCER RISK BEHIND FATTY LIVER DISEASE

A cellular enzyme long viewed as a promising target for fatty liver disease treatment may carry a dangerous hidden cost, increasing the risk of chronic liver damage and cancer later in life.

In a major new study published in Science Advances, researchers from the University of Adelaide have discovered that blocking the enzyme Caspase-2, thought to protect against fatty liver disease, can instead drive abnormal liver cell growth, inflammation and a sharply higher risk of liver cancer as we age.

The findings raise serious questions about the growing interest in Caspase-2 inhibitors as a therapeutic strategy and suggest caution is needed before targeting this pathway in humans.

Why Caspase-2 matters more than we thought

Caspase-2 has a dual role in the liver. It helps regulate fat levels while also maintaining the genetic stability of liver cells.

According to lead researcher Dr Loretta Dorstyn, from the Centre for Cancer Biology, removing that safeguard comes at a cost.

“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,” Dr Dorstyn said.

 Dr Loretta Dorstyn

What happened when the enzyme was blocked

Using genetically modified mouse models, the researchers examined what happens when Caspase-2 is absent or non-functional. The results were stark.

Liver cells in these mice became abnormally large and accumulated excessive genetic and cellular damage. Over time, this damage escalated into chronic liver inflammation and hepatitis-like disease.

“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.”

Cancer risk rises sharply with age

As the mice aged, the long-term consequences became even clearer. Animals lacking functional Caspase-2 developed spontaneous liver tumours at dramatically higher rates.

Ageing mice showed up to four times the incidence of liver cancer compared with normal mice, with tumours characteristic of hepatocellular carcinoma, the most common form of liver cancer.

Dr Dorstyn said the findings overturn the assumption that inhibiting Caspase-2 is universally beneficial.

“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.”

Implications for future drug development

Senior author Professor Sharad Kumar said the research carries a clear warning for pharmaceutical 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.”

A growing global health burden

The findings land at a critical time. Liver disease is rising worldwide, driven by ageing populations, obesity and metabolic disorders.

Liver cancer alone accounted for almost 760,000 deaths globally in 2022, according to the World Cancer Research Fund, making it the sixth most common cancer worldwide.

While the search for effective treatments for fatty liver disease continues, this study underscores a growing reality in modern medicine.

Short-term benefits do not always translate into long-term safety, and when it comes to ageing and cancer risk, the liver remembers everything.