A study from the Massachusetts Institute of Technology (MIT) has found that high-fat diets can cause mature liver cells, known as hepatocytes, to revert to a less developed, stem-cell-like state. This change may help these cells survive stressful conditions caused by fat accumulation but also makes them more likely to become cancerous.
"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, director of the Institute for Medical Engineering and Sciences (IMES), J. W. Kieckhefer Professor in IMES and the Department of Chemistry at MIT. Shalek is also affiliated with the Koch Institute for Integrative Cancer Research at MIT, the Ragon Institute of MGH, MIT and Harvard, and the Broad Institute of MIT and Harvard.
The research team included Ömer Yilmaz, an associate professor of biology at MIT; Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology; graduate student Constantine Tzouanas; former postdoc Jessica Shay; and Marc Sherman from Massachusetts General Brigham.
Their findings were published in Cell on December 22, 2025.
The study focused on how genes are regulated within liver cells when exposed to prolonged high-fat diets—a condition that can lead to steatotic liver disease. This disease results from inflammation and fat buildup in the liver and can progress to cirrhosis or cancer after years of metabolic stress.
To examine this process closely, researchers fed mice a high-fat diet and analyzed their liver cells using single-cell RNA sequencing across different stages—from early inflammation through tissue scarring up to cancer development. The analysis showed that hepatocytes began expressing genes linked with cell survival while turning off genes necessary for normal liver function.
"This really looks like a trade-off, prioritizing what's good for the individual cell to stay alive in a stressful environment, at the expense of what the collective tissue should be doing," said Tzouanas.
Nearly all mice on a high-fat diet developed liver cancer during the course of this study. Researchers noted that once hepatocytes enter an immature state—similar to stem cells—they become more prone to becoming cancerous if further mutations occur.
"These cells have already turned on the same genes that they're going to need to become cancerous. They've already shifted away from the mature identity that would otherwise drag down their ability to proliferate," Tzouanas added. "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."
Several transcription factors were identified as key regulators behind this cellular reversion. Notably, one gene targeted by an approved drug for severe steatotic liver disease was highlighted in their findings. Another potential target is SOX4—a transcription factor typically active only during fetal development or in select adult tissues but not usually present in healthy adult livers.
Researchers extended their investigation by analyzing human tissue samples taken from patients at various stages of liver disease progression—including individuals who had not yet developed cancer—and observed similar patterns: reduced expression of normal function genes alongside increased expression associated with immaturity.
"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 explained. "And if a patient has lower expression of genes that support the functions that the liver normally performs, they also survive for less time."
While it took about one year for mice in this experiment to develop cancer under these conditions—which translates into roughly 20 years in humans—the timeline may vary based on other risk factors such as alcohol use or viral infections.
The team plans further research into whether returning to healthier diets or using weight-loss drugs could reverse any changes brought about by fatty diets or whether targeting specific transcription factors could prevent diseased tissue from progressing toward cancer.
"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 work received funding from several sources including fellowships from Fannie and John Hertz Foundation and National Science Foundation Graduate Research Fellowship as well as grants from National Institutes of Health and MIT Stem Cell Initiative through Foundation MIT.
