Low Protein Diet Slows Liver Tumor Growth in Mice, Offering New Cancer Insight

Reducing protein intake may slow the growth of liver tumors in mice with impaired liver function, according to research published this week in Science Advances. The study, led by Wei-Xing Zong at Rutgers University, suggests that a buildup of ammonia, normally processed by the liver, can fuel cancer cell growth when the organ’s ability to clear waste is compromised.

Researchers found that tumors grew more rapidly in mice when ammonia clearance was hindered. Instead of being converted into urea for safe removal, excess ammonia was diverted into compounds used by cancer cells for DNA and RNA synthesis, essential for cell division. “The ammonia goes into amino acids and nucleotides, both of which tumor cells depend on for growth,” Zong explained.

The research builds on observations that patients with liver cancer often exhibit hyperammonemia – high levels of ammonia in the blood. Traditionally, this has been viewed as a consequence of liver cancer, rather than a potential contributing factor, according to Zong.

To test their hypothesis, the Rutgers team reduced the protein content in the diet of tumor-prone mice. Lower protein intake meant less nitrogen entering the liver, and reduced ammonia production. This dietary change slowed tumor growth and extended survival in two different liver cancer models, suggesting a biological effect rather than a chance occurrence.

The study also investigated the role of specific enzymes involved in ammonia clearance. Researchers systematically disabled several of these enzymes, finding that each disruption led to increased ammonia levels, larger tumors, and shorter lifespans in the mice. This suggests that the broader loss of ammonia control, rather than a defect in a single gene, is the key driver of tumor growth.

According to the National Cancer Institute, an estimated 42,240 cases of liver cancer will be diagnosed in the U.S. In 2025, resulting in 30,090 deaths. Five-year survival rates for liver and intrahepatic bile duct cancer remain low, at 22 percent. The prevalence of fatty liver disease, affecting approximately one in four adults, further underscores the potential impact of this research, as fatty liver disease can lead to liver damage and impaired function.

While current cancer care often emphasizes adequate protein intake to maintain muscle mass and strength during treatment, Zong cautions that reducing protein consumption may be beneficial for individuals with compromised liver function. Though, he stresses that drastically reducing protein intake can lead to weakness and malnutrition, and any dietary changes should be made under medical supervision.

The research team also found that low-protein feeding reduced cell division, scar-forming activity, and growth signals within the tumors themselves, supporting the idea that limiting nitrogen availability slows down the cellular processes necessary for tumor expansion. The study was supported by two NIH R01 grants focusing on the roles of glutamine synthetase and urea cycle enzymes, both critical pathways in ammonia detoxification.

Further research, including human clinical trials, is needed to determine the optimal protein intake for individuals with liver disease and cancer, and to assess the safety and efficacy of this dietary approach. The study highlights a potential new avenue for liver cancer prevention and treatment, reframing the disease as a waste-management problem where damaged tissue converts leftover nitrogen into fuel for growth.