CT scan of upper abdomen shows abnormal mass at liver, potentially cancer. (Credit: © Puwadol Jaturawutthichai | Dreamstime.com)
SAN DIEGO — Scientists at the University of California San Diego School of Medicine have uncovered a key mechanism explaining how liver cancer manages to develop despite the body’s natural defenses against tumor formation. The finding is particularly urgent given that liver cancer stands as the sixth most frequently diagnosed cancer and fourth leading cause of cancer deaths worldwide, with cases rising 25-30% in the past two decades.
Many people don’t realize that our bodies have built-in safeguards against cancer development. One such defense is cellular senescence, a state where damaged cells permanently stop dividing to prevent them from becoming cancerous. This is particularly relevant for understanding liver cancer, which often develops in people with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease that significantly increases liver cancer risk.
Previously known as non-alcoholic steatohepatitis. MASH occurs when excess fat accumulation leads to liver inflammation and damage. Currently, fatty liver disease affects 25% of adult Americans, with about 20% of those individuals having MASH,
“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” explains Michael Karin, Ph.D., Distinguished Professor in the Department of Pharmacology at UC San Diego School of Medicine, in a statement.. “When you have MASH, you either end up destroying your liver and then you need a new liver, or you progress to frequently fatal liver cancer.”
The research team used mouse models and human tissue specimens to demonstrate that diets high in fat and sugar – which can induce MASH – cause DNA damage in liver cells, forcing them into senescence. These senescent cells remain alive and metabolically active but can no longer divide. While senescence typically serves as a protective mechanism giving the body time to repair damage or eliminate damaged cells, the researchers discovered that some damaged liver cells survive this process.
Through analysis of 83 human liver cancer specimens, the researchers identified a key enzyme called FBP1 that acts as a molecular switch in this process. When liver cells become stressed or damaged due to conditions like MASH, FBP1 helps activate tumor-suppressing mechanisms. However, the team found that most liver cancers in their study had developed ways to suppress FBP1, allowing precancerous cells to escape senescence and continue dividing.
The findings also reveal concerning links between diet and DNA damage. “A poor, fast-food diet can be as dangerous as cigarette smoking in the long run,” says Karin. “People need to understand that bad diets do far more than just alter a person’s cosmetic appearance. They can fundamentally change how our cells function, right down to their DNA.”
The research suggests several potential therapeutic approaches. “There are a few possibilities for how this could be leveraged into a future treatment,” Karin notes. “One hypothesis is that a high-fat diet could lead to an imbalance in the raw materials our cells use to build and repair DNA, and that we could use drugs or nutri-chemicals to correct these imbalances. Another idea is developing new antioxidants, much more efficient and specific than the ones we have now.”
The study provides crucial insights into the relationship between aging and cancer, helping to resolve what Karin calls a paradox: while aging increases cancer risk and is associated with cellular senescence, senescence is supposed to guard against cancer. This research helps explain how cells can eventually bypass this protective mechanism.
Paper Summary
Methodology
The researchers used a comprehensive approach combining mouse experiments, human tissue analysis, and molecular biology techniques. They created genetically modified mice lacking FBP1 specifically in liver cells and fed them special diets to induce MASH-like conditions. They also collected liver cancer samples from 83 patients and analyzed protein levels using various biochemical techniques. Advanced DNA sequencing methods helped track genetic changes during cancer development.
Results
The study found that FBP1 levels were significantly reduced in 71% of human liver cancers examined. Mice lacking FBP1 developed liver tumors faster when fed harmful diets. The team identified multiple mechanisms by which cancer cells suppress FBP1, including DNA methylation and protein degradation. They also mapped out the molecular pathway through which FBP1 loss enables cancer development.
Limitations
While comprehensive, the study primarily focused on mouse models and tissue samples, which may not fully represent the complexity of human disease. The patient sample size (83) was relatively modest, and long-term follow-up data was limited. Additionally, the research didn’t explore whether restoring FBP1 function could treat established tumors.
Discussion and Takeaways
This research reveals how liver cancer cells disable natural anti-cancer mechanisms by suppressing FBP1. It explains the paradox of how liver cancer develops despite MASH triggering protective responses. The findings suggest potential new therapeutic strategies targeting FBP1 or related pathways. Additionally, the study emphasizes the profound impact of diet on cellular function and DNA integrity.
Funding and Disclosures
The research was supported by multiple National Institutes of Health grants (R01DK120714, R01DK133448, R01CA234128, R01CA281784, P01CA281819, R01DK133448, R35CA220483, DK099205, R01ES030993, R01ES032547, R01CA269919).
Publication Information
The study “FBP1 controls liver cancer evolution from senescent MASH hepatocytes” was published in Nature on January 1, 2025. The research was led by scientists at the University of California San Diego School of Medicine, with key experiments completed at West China Hospital in Chengdu, PRC, in collaboration with multiple international institutions including Curtin Health Innovation Research Institute, UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, Sanford Burnham Prebys, and the Abramson Family Cancer Research Institute.
