A new study conducted by researchers from University College London (UCL) sheds light on the devastating effects of high ammonia levels on liver cells and offers hope for those suffering from liver disease through a potential treatment. The research, published in Science Advances, provides new insights into how ammonia harms liver cells, specifically by damaging the mitochondria, which play a crucial role in both the liver’s function and the body’s ability to process ammonia. Importantly, the study also points to an existing drug, YAQ-005, which may offer a solution to prevent this cellular damage.
Ammonia buildup in the body, known as hyperammonemia, has long been recognized as a harmful consequence of liver disease, particularly cirrhosis. While the link between high ammonia levels and brain dysfunction in such patients is well documented, the specific mechanisms through which ammonia damages liver cells had remained unclear. This study is groundbreaking in that it not only identifies the direct effect of ammonia on liver cells but also provides a potential therapeutic approach using YAQ-005, an already developed drug, which is set to begin clinical trials soon.
The liver typically helps to clear ammonia from the body through a process called the urea cycle, in which ammonia is converted into urea, which is then excreted through urine. However, in patients with liver disease, especially cirrhosis, the liver’s ability to process ammonia is compromised, leading to its accumulation in the blood and brain. While this has been understood to cause cognitive dysfunction and confusion, the way in which ammonia damages the liver cells themselves remained an unsolved puzzle.
Professor Rajiv Jalan, the senior author of the study from the UCL Institute for Liver & Digestive Health, explains that the damage caused by ammonia is not confined to the liver’s ability to detoxify the body. Instead, ammonia harms the mitochondria within liver cells, which are responsible for producing the energy required for cell function. This damage to the mitochondria creates a vicious cycle: the more ammonia accumulates, the more it harms the mitochondria, and the more mitochondrial damage occurs, the more ammonia builds up in the system, resulting in a complete breakdown of liver function.
Liver cirrhosis, which affects about 100 million people worldwide, is a leading cause of hyperammonemia. Of the 100 million, about three million individuals experience episodes of confusion or even coma due to elevated ammonia levels. Alarmingly, 10 to 15 percent of these patients succumb to their condition within three months of experiencing such an episode, making effective treatments critical.
In the current study, the researchers made an important discovery. They found that elevated ammonia levels cause an increase in two proteins, RIPK1 and RIPK3, both of which are involved in mitochondrial damage and a form of cell death called necroptosis. This form of cell death, which is distinct from apoptosis, causes liver cells to die in a way that also harms surrounding organs and systems, including the immune system. Moreover, the study found that ammonia exposure activates the TLR4 signaling pathway, which alerts the immune system when pathogens are detected and plays a role in inducing the production of RIPK1.
Through a series of experiments on mouse models, the research team observed that the increased production of RIPK1 and RIPK3 proteins corresponded with worsening liver damage, scarring, and cell death. This was the first demonstration that ammonia directly contributes to liver injury by inducing mitochondrial dysfunction and cell death.
Promisingly, the researchers tested two drugs to intervene in this harmful process. The first drug, RIPA-56, was designed to block the RIPK1 pathway and prevent the mitochondrial damage and subsequent cell death. The second drug, YAQ-005, targeted the TLR4 signaling pathway to stop the activation of RIPK1 proteins. When administered to the mice, both drugs showed promise in significantly reducing liver injury and cell death, with YAQ-005 proving particularly effective in protecting the liver from the toxic effects of ammonia.
YAQ-005, which was previously known as TAK-242, has already been patented by UCL Business (UCLB), the commercialization arm of UCL. It is currently undergoing a Phase II clinical trial for acute-on-chronic liver failure, a condition related to cirrhosis that involves liver dysfunction and a rapid decline in liver function. This trial, which is scheduled to begin recruiting patients in mid-2025, could provide the first human evidence of YAQ-005’s ability to prevent the liver damage caused by hyperammonemia.
The study’s authors believe that YAQ-005 could also have broader applications. They suggest that it could be beneficial for children with urea-cycle disorders, a group of rare genetic conditions in which the urea cycle is impaired, leading to elevated ammonia levels in the body. These conditions are often associated with mitochondrial dysfunction, a problem that YAQ-005 has the potential to alleviate.
Dr. Annarein Kerbert, the first author of the study from the UCL Institute for Liver & Digestive Health and Leiden University Medical Centre, emphasized the significance of the findings, noting that there are currently no targeted drugs available to prevent the progression of chronic liver disease. “In this study, we have shown the potential of the drug YAQ-005 in protecting the liver from the toxic effects of hyperammonemia. We therefore believe that this could be a potential novel therapy for disease progression in cirrhosis,” Kerbert stated. “Our aim is to investigate this further in proof-of-concept clinical studies.”
Troels Jordansen, CEO of Yaqrit, the company that licensed YAQ-005 from UCL and is conducting the Phase II trials, added, “We are looking forward to advancing this innovative drug, licensed from UCL, into phase II trials in acute-on-chronic liver failure. This is a complicated life-threatening condition and there is an urgent need for new approaches.”
The development of YAQ-005 represents a significant step forward in the fight against liver disease, particularly cirrhosis, which remains a leading cause of death worldwide. The promise of this drug offers hope for millions of individuals suffering from conditions related to liver failure, and as clinical trials progress, it may pave the way for novel therapies that address not only the symptoms of hyperammonemia but the underlying mechanisms of liver injury.
As liver diseases continue to affect a growing number of people globally, understanding the precise mechanisms behind ammonia-induced liver damage and finding ways to counteract them is critical. The potential of YAQ-005 to block these processes could change the treatment landscape for liver disease, offering patients a new avenue for hope. This study not only offers a deeper understanding of liver disease but also highlights the importance of drug repurposing in the search for treatments for complex, life-threatening conditions. If clinical trials confirm the findings from this study, YAQ-005 may become a cornerstone in the treatment of liver failure, improving outcomes and quality of life for many patients.
More information: Annarein Kerbert et al, Hyperammonemia induces programmed liver cell death, Science Advances (2025). DOI: 10.1126/sciadv.ado1648. www.science.org/doi/10.1126/sciadv.ado1648