A Promising Fatty Liver Treatment May Actually Trigger Cancer

A new study suggests that suppressing a cellular enzyme long considered protective against fatty liver disease could have unexpected long-term consequences.

Scientists have uncovered a troubling tradeoff in the liver. An enzyme called Caspase-2 has attracted attention as a possible target for fatty liver disease, but new evidence suggests shutting it down could make the liver more vulnerable over time. Instead of offering lasting protection, blocking this enzyme may increase the risk of chronic liver injury, scarring, and cancer with age.

In a study published in Science Advances, researchers at the University of Adelaide found that losing Caspase-2 disrupts the normal control of liver cell growth. That breakdown set off a chain reaction in mice, including inflammation, fibrosis, and a sharply higher risk of liver cancer.

The findings complicate the idea of using Caspase-2 inhibitors to treat or prevent fatty liver disease. A strategy that may appear helpful early on could carry serious long-term consequences later in life.

Caspase-2 and Liver Cell Stability

According to lead researcher Dr. Loretta Dorstyn of the Centre for Cancer Biology, Caspase-2 helps protect the genetic stability of liver cells. It also plays a separate role in regulating fat in the liver, making it relevant to both metabolic disease and cancer biology.

“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.

That balance appears to be critical. The liver is one of the body’s most resilient organs, but it depends on tight control over which cells survive and which damaged cells are removed. The new study suggests Caspase-2 is part of that quality control system.

Evidence From Mouse Models

Using genetically modified mice, the team examined what happens when Caspase-2 is missing or no longer functions properly. In those animals, liver cells became unusually large and showed extensive genetic and cellular damage.

“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.”

Older mice without working Caspase-2 developed spontaneous liver tumors at much higher rates than normal mice, with up to four times the incidence of liver cancer. The cancers were characteristic of hepatocellular carcinoma, the most common form of liver cancer.

Dr. Dorstyn said the results overturn the idea that suppressing 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.”

Why the Results Matter

The study arrives as liver disease becomes an increasingly urgent health issue worldwide, fueled by aging populations, obesity, and metabolic disorders. According to the World Cancer Research Fund, liver cancer caused nearly 760,000 deaths worldwide in 2022, making it the sixth most common cancer globally.

Senior author Professor Sharad Kumar said the research has important 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.”

Reference: “Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice” by Loretta Dorstyn, Yoon Lim, Jack Scanlan, Emma McLennan, Dylan De Bellis, Michael Katschner, John Finnie, Samantha Emery-Corbin, Jumana Yousef, Laura F. Dagley, Chung H. Kok, Sonia S. Shah, Chiaki Takahashi, Mark A. Febbraio and Sharad Kumar, 1 January 2026, Science Advances.
DOI: 10.1126/sciadv.aeb2571

Funding: National Health and Medical Research Council

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