HQ Team
January 2, 2025: Scientists at the University of California San Diego School of Medicine have made deeper inroads in understanding the progression of fatty liver disease to a more severe form of cancer known as metabolic dysfunction-associated steatohepatitis (MASH). This research, published in Nature, highlights the critical role of cellular metabolism and DNA damage in this progression.
Liver cancer is the sixth most commonly diagnosed cancer globally and is responsible for a substantial number of cancer-related deaths. The incidence of hepatocellular carcinoma (HCC), the most prevalent type of liver cancer, has surged by 25-30% over the past two decades, largely due to rising cases of fatty liver disease, which currently affects about 25% of adults in the U.S. Approximately 20% of those with fatty liver disease develop MASH, significantly increasing their risk of developing HCC. Primary liver cancer was among the top three causes of cancer death in 46 countries in 2020. And among the top five causes of cancer death in nearly 100 countries, including several high-income countries.
Fatty liver pathway…
Dr. Michael Karin, a distinguished professor at UC San Diego, emphasized that the pathway from fatty liver disease to MASH and ultimately to liver cancer is common. “Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” said Michael Karin, Ph.D., Distinguished Professor in the Department of Pharmacology at UC San Diego School of Medicine. “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.”
The study utilized mouse models and human tissue samples to demonstrate that diets high in fat and sugar lead to DNA damage in liver cells. This damage pushes cells into a state called senescence, where they remain alive but can no longer divide. While senescence typically serves as a protective mechanism against cancer by allowing for cellular repair or removal, some damaged liver cells evade this process and may eventually proliferate uncontrollably.
Diet-induced DNA damage
The research team found DNA analysis of many tumors confirmed that they arise from these damaged hepatocytes, establishing a direct connection between diet-induced DNA damage and cancer development. This insight opens potential avenues for new treatments aimed at preventing or reversing DNA damage in individuals with MASH.
Dr. Karin suggested that future therapies could focus on DNA repair or developing more effective antioxidants to prevent cellular stress. “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,” said Karin. “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, and using those could help block or reverse the cellular stress that causes DNA damage in the first place.”
Furthermore, the study sheds light on the relationship between aging and cancer risk, revealing how senescence can paradoxically contribute to cancer development despite its protective role.
This research underscores the importance of dietary choices in influencing cellular health and cancer risk. Dr. Karin noted that unhealthy diets could have long-term effects on cellular function comparable to those caused by smoking.
Read the full study in Nature.
