Researchers warn of cancer risk from fatty liver treatment

  Blocking a key cellular enzyme, an approach thought to offer protection from fatty liver disease, may actually increase the risk of chronic liver damage and cancer as people age, Australian researchers said on Tuesday (13/1).

Published in the journal Science Advances, the study found that the loss of the Caspase-2 enzyme triggers abnormal growth in liver cells, leading to inflammation, fibrosis and a significant increase in the risk of liver cancer, according to a press release from the University of Adelaide, Australia.

The findings challenge the growing interest in Caspase-2 inhibitors as a potential therapeutic strategy to treat and/or prevent fatty liver disease and highlight the need for caution when targeting this pathway, according to the statement.

Caspase-2 plays a crucial role in maintaining the genetic stability of liver cells while also having an independent role in controlling fat levels in the liver, said lead researcher Loretta Dorstyn of the Center for Cancer Biology.

"Liver cells normally have extra copies of genetic material, known as polyploidy, and although this element can help the liver cope with stress, our study shows that without the Caspase-2 enzyme, abnormally high levels of polyploidy in the liver can trigger damage," said Dorstyn.

In mice that lack the enzyme Caspase-2 or have a version of the enzyme that no longer works, liver cells are abnormally large with excessive amounts of genetic and cellular damage, the researchers said.

"Over time, these mice developed chronic liver inflammation and characteristics of liver disease that resemble hepatitis, including scarring, oxidative damage, and the type of cell death associated with inflammation," Dorstyn said.

In the study, older animals were more likely to develop liver cancer.

The study also showed that aging mice lacking a functional Caspase-2 enzyme developed spontaneous liver tumors at a much higher rate than normal mice, with up to a fourfold increased incidence of liver cancer, which is characteristic of hepatocellular carcinoma.

The findings challenge the assumption that inhibiting Caspase-2 is universally beneficial, suggesting that the enzyme is essential for eliminating damaged liver cells as we age, and without it, those cells would accumulate and lead to cancer, Dorstyn said.

The authors say the research has important implications for drug development.