A high-fat diet does more than overload the liver with fat — it can fundamentally alter liver cells in ways that quietly increase cancer risk. New research from MIT shows that prolonged exposure to fatty foods pushes liver cells into a survival mode, leaving them less functional and more vulnerable to tumour formation.
Mature liver cells, or hepatocytes, normally perform specialised metabolic and detoxifying functions. But when repeatedly exposed to a high-fat diet, these cells revert to a more primitive, stem-cell-like state. This transformation helps them endure metabolic stress caused by excess fat but simultaneously makes them more prone to becoming 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,” explained Alex K. Shalek, director of the Institute for Medical Engineering and Sciences at MIT.
The researchers used single-cell RNA sequencing to track gene activity in mice fed a high-fat diet. Early on, hepatocytes activated genes that prevent programmed cell death and promote cell growth. At the same time, genes responsible for normal liver functions, including metabolism and protein secretion, gradually shut down. “This looks like a trade-off, prioritising what’s good for the individual cell at the expense of what the liver as a whole should be doing,” noted co-author Constantine Tzouanas.
Immature liver cells are particularly susceptible to cancer. Once they acquire damaging mutations, they have already activated genes that facilitate rapid growth, giving cancer a “head start.” Several key transcription factors, including SOX4, were identified as regulators of this cellular shift. Drugs targeting some of these pathways, such as thyroid hormone receptor modulators or HMGCS2 activators, are currently being explored for fatty liver disease treatment.
Evidence from human liver tissue confirmed similar gene patterns. Genes promoting cell survival were elevated, while those supporting normal liver function declined. Patients with higher expression of these stress-response genes tended to have shorter survival after tumour development, highlighting the relevance of diet-driven cellular changes to human health.
Looking ahead, researchers plan to study whether lifestyle interventions — such as healthier diets or weight-loss medications like GLP-1 agonists — can reverse the cellular changes induced by high-fat diets. “We now have new molecular targets and a better understanding of the biology, which could open avenues to improve patient outcomes,” Shalek said.
This research underscores the hidden dangers of long-term high-fat consumption, demonstrating that diet can reshape liver cells at a molecular level, quietly increasing cancer risk over decades.
