MIT Reveals How High-Fat Diets Quietly Prime the Liver for Cancer

A fatty diet doesn’t just damage the liver — it rewires its cells in ways that give cancer a dangerous head start.

Eating a diet high in fat is one of the strongest known risk factors for liver cancer. New research from MIT explains why, showing that fatty diets can fundamentally change how liver cells behave in ways that make cancer more likely to develop.

The study found that when the liver is exposed to a high-fat diet, mature liver cells called hepatocytes undergo a striking shift. Instead of maintaining their specialized roles, these cells revert to a more primitive, stem-cell-like state. While this transformation helps the cells cope with the ongoing stress caused by excess fat, it also leaves them far more vulnerable to becoming cancerous over time.

“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,” says Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES), the J. W. Kieckhefer Professor in IMES and the Department of Chemistry, and a member of 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 team also pinpointed several transcription factors that appear to drive this cellular regression. Because these molecules help control whether liver cells stay mature or revert to an immature state, they may offer promising targets for future drugs aimed at reducing cancer risk in vulnerable patients.

Shalek; Ömer Yilmaz, an MIT associate professor of biology and a member of the Koch Institute; and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology, are the senior authors of the study, which appears today in Cell. MIT graduate student Constantine Tzouanas, former MIT postdoc Jessica Shay, and Massachusetts General Brigham postdoc Marc Sherman are the co-first authors of the paper.

What Happens to Liver Cells Under Long-Term Fat Stress

High-fat diets are known to promote inflammation and fat buildup in the liver, leading to a condition called steatotic liver disease. This disorder can also result from other long-term metabolic stresses, including heavy alcohol use, and may progress to cirrhosis, liver failure, and eventually cancer.

To better understand what drives this progression, the researchers focused on how liver cells respond at the genetic level when exposed to a high-fat diet, especially which genes are activated or shut down as damage accumulates over time.

The team fed mice a high-fat diet and used single-cell RNA-sequencing to analyze liver cells at multiple stages of disease development. This approach allowed them to track changes in gene activity as the animals moved from early inflammation to tissue scarring and, ultimately, liver cancer.

Early in the process, hepatocytes began activating genes that promote survival under stress. These included genes that reduce the likelihood of cell death and encourage continued cell division. At the same time, genes essential for normal liver function, such as those involved in metabolism and protein secretion, were gradually switched off.

“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,” Tzouanas says.

Some of these shifts occurred quickly, while others developed more slowly. In particular, the decline in metabolic enzyme production unfolded over a longer period. By the end of the study, nearly all mice on the high-fat diet had developed liver cancer.

Why Immature Cells Are More Vulnerable to Cancer

According to the researchers, liver cells that revert to a less mature state appear to be especially susceptible to cancer if they later acquire harmful mutations.

“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 says. “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.”

The team also identified specific genes that help coordinate this shift back to an immature state. During the course of the study, a drug targeting one of these genes (thyroid hormone receptor) was approved to treat a severe form of steatotic liver disease known as MASH fibrosis. In addition, a drug that activates another enzyme highlighted in the research (HMGCS2) is currently being tested in clinical trials for steatotic liver disease.

Another potential drug target identified by the researchers is a transcription factor called SOX4. This factor is typically active during fetal development and in only a limited number of adult tissues (but not the liver), making its reactivation in liver cells particularly notable.

Evidence From Human Liver Disease

After observing these effects in mice, the researchers examined whether the same patterns could be found in people. They analyzed liver tissue samples from patients at various stages of liver disease, including individuals who had not yet developed cancer.

The human data closely matched the findings in mice. Over time, genes required for healthy liver function declined, while genes linked to immature cell states became more active. Using these gene expression patterns, the researchers were also able to predict patient survival outcomes.

“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 says. “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 cancer developed within about a year in mice, the researchers believe the same process unfolds much more slowly in humans, potentially over a span of roughly 20 years. The timeline likely varies depending on factors such as diet, alcohol use, and viral infections, all of which can encourage liver cells to revert to an immature state.

Can the Damage Be Reversed?

The researchers now plan to explore whether the cellular changes triggered by a high-fat diet can be reversed. Future studies will test whether returning to a healthier diet or using weight-loss medications such as GLP-1 agonists can restore normal liver cell function.

They also hope to further evaluate the transcription factors identified in the study as possible drug targets to prevent damaged liver tissue from progressing to 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 says.

Reference: “Hepatic adaptation to chronic metabolic stress primes tumorigenesis” by Constantine N. Tzouanas, Jessica E.S. Shay, Marc S. Sherman, Adam J. Rubin, Benjamin E. Mead, Tyler T. Dao, Junyan Tao, Brandon M. Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D. Mana, Kellie E. Kolb, Chad Walesky, Brian J. Pepe-Mooney, Colton J. Smith, Sanjay M. Prakadan, Michelle L. Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L. Winston, Woo-Jeong Jeong, Katherine J. Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P. Monga, Georg M. Lauer, Wolfram Goessling, Ömer H. Yilmaz and Alex K. Shalek, 22 December 2025, Cell.
DOI: 10.1016/j.cell.2025.11.031

The research was funded, in part, by a Fannie and John Hertz Foundation Fellowship, a National Science Foundation Graduate Research Fellowship, the National Institutes of Health, and the MIT Stem Cell Initiative through Foundation MIT.

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