Researchers pinpoint how fatty liver disease progresses to liver cancer, offering fresh insights into prevention and treatment. The study highlights the critical role of diet and DNA damage in cancer development.
Researchers led by the University of California San Diego School of Medicine have made pivotal discoveries about the progression of fatty liver disease to liver cancer in a study published in the journal Nature. Their findings expose a significant relationship between cellular metabolism and DNA damage, providing promising directions for preventing and treating hepatocellular carcinoma (HCC).
The prevalence of HCC, the most common type of liver cancer, has surged by 25-30% over the past two decades. This increase is largely attributed to a rise in fatty liver disease, now affecting approximately 25% of American adults.
More alarmingly, around 20% of those with fatty liver disease suffer from metabolic dysfunction-associated steatohepatitis (MASH), which significantly elevates the risk of developing HCC.
“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” co-corresponding author Michael Karin, a Distinguished Professor of Pharmacology at UC San Diego School of Medicine, said in a news release. “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, but we still don’t understand what’s happening at the subcellular level during this process.”
Utilizing a blend of mouse models, human tissue samples and comprehensive genomic analysis, the researchers demonstrated that diets high in fats and sugars trigger DNA damage in liver cells. This damage forces liver cells into a state of senescence, where they remain metabolically active but cease to divide. While senescence typically allows the body to repair or eliminate damaged cells, some liver cells bypass this safeguard and remain viable.
These cells, described by Karin as “like ticking time bombs,” retain the potential to proliferate and eventually turn cancerous.
“Comprehensive genomic analyses of tumor DNA indicate that they originate from liver cells damaged by MASH, emphasizing a direct link between diet-induced DNA damage and the development of cancer,” co-author Ludmil Alexandrov, an associate professor of cellular and molecular medicine and bioengineering at UC San Diego, said in the news release.
The results indicate that targeting DNA damage with new drug therapies could offer a novel approach to preventing liver cancer, especially for those suffering from MASH.
“There are a few possibilities for how this could be leveraged into a future treatment, but it will take more time and research to explore these ideas,” added Karin.
He suggested that correcting imbalances in cellular DNA repair mechanisms or developing advanced antioxidants could counteract the DNA damage caused by poor diets.
Beyond its promise for new therapeutic strategies, the research also deepens our understanding of the link between aging, poor diet and cancer development.
“We know that aging increases the risk of virtually all cancers and that aging is associated with cellular senescence, but this introduces a paradox since senescence is supposed to guard against cancer,” Karin added. “This study helps reveal the underlying molecular biology that allows cells to re-enter the cell cycle after undergoing senescence, and we believe that similar mechanisms could be acting in a wide range of cancers.”
Public health could also benefit from these findings by emphasizing the long-term dangers of unhealthy dietary habits.
“A poor, fast-food diet can be as dangerous as cigarette smoking in the long run,” concluded 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.”
This research represents a significant leap towards understanding the profound impact of diet on cellular health and cancer development, fostering hope for future preventative and therapeutic strategies against liver cancer.