A high-fat diet does far more than overload the liver with fat; it pushes liver cells into a survival mode that quietly sets the stage for cancer, new research from MIT has found. The study, published in Cell, shows that prolonged exposure to fatty foods drives mature liver cells (hepatocytes) to revert to a more primitive, stem‑cell‑like state that helps them endure metabolic stress but makes them far more prone to tumour formation over time.
Using a mouse model of steatotic liver disease, researchers fed animals a high-fat diet and tracked liver changes over time with single‑cell RNA sequencing, following the progression from inflammation and scarring to full‑blown cancer. Early in the disease course, hepatocytes switched on genes that promote cell survival and growth while gradually shutting down genes responsible for core liver functions such as metabolism and protein secretion, a trade‑off that preserves individual cells but undermines overall organ health.
“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 senior author Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES) at MIT. Co‑senior authors included Omer Yilmaz, associate professor of biology at MIT, and Wolfram Goessling, co‑director of the Harvard‑MIT Program in Health Sciences and Technology, with the work led by first authors Constantine Tzouanas, Jessica Shay and Marc Sherman.
By the end of the experiment, nearly all mice on the high-fat diet had developed liver cancer, and analysis showed that immature‑like hepatocytes were especially likely to become malignant once they acquired additional mutations. “These cells have already turned on the same genes that they’re going to need to become cancerous… once a cell picks up the wrong mutation, then it’s really off to the races,” Tzouanas noted.
The team also identified transcription factors and signalling pathways that appear to coordinate the shift back to an immature state, highlighting several potential drug targets. One target, the thyroid hormone receptor, is already inhibited by an approved drug for MASH fibrosis, while an agent that activates the enzyme HMGCS2 is in clinical trials for steatotic liver disease; another factor, SOX4, emerged as a particularly promising candidate because it is normally active only in fetal development and a few adult tissues, not the liver.
To test the relevance in humans, the researchers examined liver samples from patients at different stages of disease, including those without cancer, and found gene expression patterns similar to those observed in mice. Patients with higher expression of pro‑survival genes induced by a high‑fat diet, and lower expression of normal liver function genes, had poorer survival once tumours developed, suggesting these molecular signatures may help predict prognosis.
While mice progressed to cancer within about a year, the investigators estimate the same sequence of changes in humans likely unfolds over roughly two decades, influenced by diet, alcohol use and viral infections that also push hepatocytes toward an immature state. The group now plans to explore whether these cellular changes can be reversed by returning to a healthier diet, using weight‑loss therapies such as GLP‑1 agonists, or targeting the newly identified transcription factors to prevent damaged liver tissue from progressing to cancer.
