A long-term buildup of fat in the liver may do more than interfere with metabolism. It may also change liver cells in ways that make them more vulnerable to cancer later in life, according to new research from Massachusetts Institute of Technology.
The study, published in Cell, examined how chronic exposure to a high-fat diet affects liver cells at the molecular level. The findings suggest that prolonged metabolic stress can push mature liver cells into a more immature state that helps them survive short-term stress but may increase their susceptibility to cancer-causing mutations over time.
Most of the experiments were conducted in mice, with additional analysis of human liver tissue used to assess whether similar biological patterns appear in people with liver disease. While the timeline differs between species, the researchers estimate that in humans, these changes likely develop gradually over decades rather than months or years.
The liver plays a central role in processing fats, sugars and other nutrients. When excess fat accumulates in liver tissue, it can lead to steatotic liver disease, a condition that often develops silently and is becoming increasingly common. Over time, this ongoing metabolic strain creates a stressful environment for liver cells.
In the study, researchers fed mice a high-fat diet and tracked how individual liver cells responded using single-cell RNA sequencing. As liver disease progressed from inflammation to scarring and eventually cancer, the scientists observed a consistent shift in liver cell behavior. Mature hepatocytes, which normally carry out essential liver functions, began turning on genes that promote survival and growth while turning off genes involved in normal metabolic activity. In effect, the cells reverted to a more stem-like, immature state.
“If cells are forced to deal with a stressor, such as a high-fat diet, over and over again, they will do things that will help them survive, but at the risk of increased susceptibility to tumorigenesis,” said Alex K. Shalek, a senior author of the study.
This shift appears to be a biological tradeoff. While it may help individual cells endure chronic stress, it also leaves them closer to a cancer-ready state. Cells in this immature condition already express many of the same genes they would later rely on to proliferate rapidly if cancer-driving mutations occur.
“Once a cell picks up the wrong mutation, then it’s really off to the races and they’ve already gotten a head start on some of those hallmarks of cancer,” said lead author Constantine Tzouanas.
By the end of the study, nearly all of the mice on the high-fat diet had developed liver cancer.
To see whether similar processes might occur in people, the researchers analyzed gene expression data from human liver tissue collected at different stages of liver disease, including samples from patients who had not yet developed cancer. The patterns closely mirrored what the scientists observed in mice. As disease progressed, genes tied to normal liver function declined, while genes associated with immature, survival-focused states increased. Those patterns were also linked to worse survival after cancer developed.
“Patients who had higher expression of these pro-cell-survival genes that are turned on with high-fat diet survived for less time after tumors developed,” Tzouanas said.
The findings help explain why long-standing liver disease is such a strong risk factor for liver cancer and why prevention often needs to begin years before cancer appears. They also underscore that the risk is not driven by a single nutrient in isolation. The study does not suggest that eating fat alone causes cancer, nor does it distinguish between different types of fats or overall dietary patterns. Instead, it points to the cumulative effects of chronic metabolic stress and sustained fat accumulation in the liver.
In everyday life, that stress is shaped by multiple factors, including overall diet quality, calorie balance, alcohol intake, physical activity, underlying metabolic conditions and genetics. The authors also note that some of the cellular changes they observed may be reversible.
Future research will explore whether returning to a more balanced diet or using weight-loss medications such as GLP-1 receptor agonists can shift liver cells back toward a healthier state.
Several molecular targets identified in the study are already being explored in treatments for advanced liver disease, offering potential new strategies to reduce cancer risk in people with long-standing liver damage.
“We now have all these new molecular targets and a better understanding of what is underlying the biology, which could give us new angles to improve outcomes for patients,” Shalek said.
This research was supported by the National Institutes of Health, the National Science Foundation, the MIT Stem Cell Initiative and other academic funding sources.