Dietary Protein as a Modifiable Risk Factor in Liver Cancer, With Wei-Xing Zong, PhD

Liver cancer, most commonly hepatocellular carcinoma (HCC), remains one of the deadliest malignancies worldwide, frequently developing in the setting of chronic liver disease. As the liver’s central role in metabolism becomes increasingly recognized in cancer biology, researchers have sought to better understand how disruptions in nutrient processing and waste detoxification may contribute to tumor development and progression.

In a recent study published in Science Advances, investigators from Rutgers University identified a metabolic vulnerability linked to impaired ammonia detoxification. When the liver’s urea cycle enzymes are downregulated, ammonia generated from dietary protein is not efficiently cleared. Rather than remaining a passive toxin, excess ammonia can be recycled into amino acids and nucleotides that fuel tumor growth, effectively turning metabolic waste into a resource for cancer cells.

Using preclinical models, the team demonstrated that impaired ammonia clearance accelerated tumor burden and reduced survival. Of note, lowering dietary protein reduced ammonia levels, slowed tumor growth, and improved outcomes in these models, suggesting that nitrogen load may directly influence liver cancer progression.

For additional insight into his team’s research and the clinical significance of their findings, the editorial team of HCPLive Hepatology spoke with Wei-Xing Zong, PhD, Distinguished Professor and Chair of the Department of Chemical Biology at Rutgers University, in the following Q&A:

HCPLive: What clinical questions or uncertainties about ammonia were you seeking to address in your research?

Zong: For a long time, clinicians have observed that patients with liver cancer often suffer from hyperammonemia, so high ammonia levels in their body. Traditionally, this has been viewed as a symptom of liver failure, as a consequence of patients getting liver cancer, instead of considering whether this may be a causal factor for liver cancer. It’s also been observed that in liver cancer patients, the ammonia detoxification enzymes, which are called urea cycle enzymes, they're often turned off. So, why is that? Whether that plays a role in liver cancer development that's also not known. And then finally, whether there are ways of intervening this, you know, is also unclear, so that was the question that we're trying to target or address.

HCPLive: What are some of the key findings you report?

Zong: We were trying to address the question three fold. One was to determine whether the increased ammonia level is a cause for liver cancer. And also, if the answer is yes, what does ammonia do? What role does ammonia play in the cancer development process? And finally, whether there are ways to clinically target this problem. So to address this, we have used a system that we can manipulate the urea cycle enzymes, the ammonia detoxification enzymes in the healthy liver. We saw that by down regulating or by inhibiting these enzymes, the animals we did this in, the mouse models of liver cancer, the animals develop liver cancer much faster. Then we decided, where does the ammonia go? By getting rid of this cycle, the ammonia detoxification enzymes, ammonia accumulates in the animals, and then we determine where does ammonia go, right in terms of the biochemical pathways. So we found ammonia now gets shown to the synthesis of certain proteins and also the nucleic acid, because nucleic acids like DNA, RNA, contain nitrogen, so that's where the ammonia can contribute to that will help tumor cell growth. And then lastly, we also try it the other way. So if we find increased ammonia is really helping the tumor cells to grow, and then, whether by reducing or minimizing the ammonia level, whether we can kind of suppress the tumor growth, which we tried by lowering the dietary protein level, we did see a quite striking benefit of reducing liver cancer development.

HCPLive: Do you see a role for ammonia levels or urea cycle dysfunction as biomarkers for HCC risk or progression?

Zong: From our study, we would think the ammonia levels and also urea cycle dysfunction, the decreased expression of those enzymes, look like promising biomarkers for HCC risk assessment, especially in the patients with chronic liver disease, because often they also have dysfunctional ammonia detoxification enzymes. So we would say the biological rationale is pretty strong there, and higher ammonia levels definitely are associated with worse liver function, more aggressive tumor biology, at least in our preclinical models. However, with that, we also should be a little careful with this. Although this concept is very attractive, there could also be issues such as specificity issues, because many other liver conditions other than liver cancer may also cause this increased ammonia level. There are also certain medical conditions like infection, sarcopenia, like muscle waste, or certain medications. For example, even the medications for treating certain diseases can also cause the disturbance of the ammonia level. In that sense, we cannot solely rely on just ammonia level. We think it's better to use it together to stratify with other markers as a combination.

HCPLive: How do we reconcile current standard practices on protein intake from clinical guidelines with these new mechanistic findings?

Zong: The recommendation for many types of patients, including liver disease patients, is to use high protein to maintain the muscle mass and to maintain a strong enough immune system. So how can we reconcile this if we suggest that by lowering dietary protein, you can reduce the risk of liver cancer? We've been thinking about this, and there are several thoughts that we have. So one important thought is that the timing of intervention actually could be very important. For lowering the cancer risk, maybe it's important to specifically recommend this in the patients who already show the signs of early stage of liver cancer, or the patients who already are carrying the oncogenic mutations that can be detected. We think that in this more specific group of patients, lowering the dietary dietary protein could be a good, effective strategy. Another important idea I think many people are actually using now is not just to look at the quantity of the protein, but also the quality of protein could be very important. For example, the protein from plant or dairy resources could be healthier than protein from red meat, so that's another consideration. There are also certain amino acids in the protein, for example, the branched chain amino acids, that are considered low ammonia producing amino acids, so they may be healthier than the high ammonia producing amino acids. We think by looking at this by target, by targeting a specific group of patients, and by considering these different sources of proteins or different types of amino acids, this can help reconcile the idea of the trade off of getting sarcopenia or reducing cancer risk.

HCPLive: Beyond diet, what therapeutic opportunities does this study point to, and which seem most realistic for clinical translation?

Zong: There are several methods that we can consider in addition to lowering dietary protein. One is to use the chemical or pharmacological scavengers of ammonia. These are the chemicals that combine to form ammonia and then convert them into the non-toxic form of nitrogen, therefore, now they don't get to be used by the tumor cells. Another way is, as we know that most of the ammonia in our body is produced in the gut by gut microbiome and certain bacteria in the gut, certain antibiotics can be used just to wipe out the gut microbiome, and then that can help reducing the ammonia production in our body. Then, thinking about the whole molecular pathways, we were talking about how ammonia can be imported into cancer cells, or ammonia in the cancer cells can be converted into other forms of metabolites, for example, other amino acids or nucleotides. Then we can think of ways of incubating these other ammonia importers, or the enzymes that convert ammonia to these metabolites that are used by the tumor cells. By incubating these enzymes, we can also try to intervene with this whole ammonia pathway. Finally, by suppressing the enzymes that can convert ammonia into nucleotides, or by converting by activating the growth signaling, such as mTOR signaling or a KT pathway, these can also help reduce the effect of ammonia in promoting tumor growth.

Editors’ Note: Zong reports no relevant disclosures.

References

1. Han X, Shen J, Yan J, et al. Impaired nitrogenous waste clearance promotes hepatocellular carcinoma. Sci Adv. 2026;12(2):eaec0766. doi:10.1126/sciadv.aec0766

2. Rutgers. How a Simple Dietary Change May Slow Liver Cancer in At-Risk Patients. January 9, 2026. Accessed March 2, 2026. https://www.rutgers.edu/news/how-simple-dietary-change-may-slow-liver-cancer-risk-patients