Eating too much fatty food for long periods can seriously damage the liver. Now, researchers at MIT have discovered how this damage happens at the cellular level—and why it increases the risk of liver cancer.
In a new study published in the journal Cell, the scientists found that when the liver is exposed to high-fat diets over time, it begins to change in dangerous ways. Normally, the liver is full of specialized cells called hepatocytes. These cells perform important tasks, such as breaking down food, producing proteins, and filtering toxins.
But under the stress of a fatty diet, these mature cells start to act differently. Instead of staying specialized, they shift into a more basic or “stem-like” state. This change helps the cells survive in a stressful environment, but it also makes them more likely to become cancerous later.
This process is like a trade-off. The liver cells become tougher and more resistant to damage, but in doing so, they lose some of the features that keep them stable and safe. This increases the chance that, if they later get a harmful mutation, they will turn into cancer cells.
To understand this better, the MIT team fed mice a high-fat diet and studied their liver cells over time using a tool called single-cell RNA sequencing. This allowed them to see how the activity of different genes changed as liver damage got worse.
Early on, the liver cells began switching on genes that help them survive, while turning off genes responsible for normal liver functions. These changes happened slowly, but eventually, nearly all of the mice developed liver cancer.
One of the study’s main findings is that immature liver cells—those in the stem-like state—are much more likely to become cancerous if they acquire damaging mutations. These cells have already turned on many of the genes they need to start growing quickly and forming tumors. So once a mutation happens, the cells are already one step closer to cancer.
The researchers also found some specific genes and proteins that seem to control this shift in liver cell behavior. These may become targets for future drugs. One of these targets, called SOX4, is usually only active during early development and isn’t found in healthy adult liver tissue. Its appearance in stressed liver cells is a warning sign.
In another interesting twist, one of the genes identified in the study has already been targeted by a drug approved for a serious form of liver disease called MASH fibrosis. Another potential target is currently being tested in clinical trials.
To see if these same changes happen in humans, the researchers looked at liver tissue samples from people with various stages of liver disease.
They found that the same harmful patterns—declining liver function and rising signs of immature cell states—were present. People whose liver cells showed more of these survival-focused, stem-like features tended to have worse outcomes after developing cancer.
In mice, liver cancer developed within a year of a high-fat diet. In humans, the same process likely takes around 20 years, depending on diet and other risk factors such as alcohol use or viral infections.
The research team is now asking a hopeful question: can the damage be reversed? Future studies will look at whether switching to a healthier diet or using weight-loss drugs like GLP-1 agonists can help liver cells return to their normal, stable state. They also want to test new drugs that could target the genes involved in the harmful changes.
This study offers a deeper understanding of how diet affects liver health and cancer risk. It also gives scientists and doctors new ideas for how to treat or even prevent liver cancer caused by long-term exposure to unhealthy foods.
If you care about liver health, please read studies that refined fiber is link to liver cancer, and the best and worst foods for liver health.
For more health information, please see recent studies about how to boost your liver naturally, and simple ways to detox your liver.
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