During regeneration, the liver converts toxic ammonia into a substance that promotes growth
An international team of scientists led by the Institute of Biotechnology of the Czech Academy of Sciences at the BIOCEV center has elucidated a key mechanism that enables extremely rapid liver regeneration. A study published in the prestigious journal Nature Communications shows that during regeneration, the liver uses toxic ammonia for its renewal. It converts it into glutamine, a substance necessary for the production of DNA and RNA during rapid cell division.
The liver is unique among human organs in its ability to fully restore its weight and function even after significant damage. After removing up to a third of its volume, it can regrow to its original size in about ten days and create hundreds of millions of new cells – a rate that exceeds most types of cancer. Unlike tumors, however, this growth stops once the original size is reached.
"Liver regeneration is one of the fastest and most precisely regulated growth processes in biology. We wanted to understand how liver cells ensure they have enough molecular building blocks to replicate their DNA," explains Jiří Neužil, head of the Molecular Therapy Laboratory at the Institute of Biotechnology of the Czech Academy of Sciences (BTÚ AV ČR) and lead author of the study in Nature Communications.
Transition from detoxification to synthesis
The researchers found that during regeneration, there is a dramatic change in liver metabolism. Instead of the usual detoxification of ammonia via the urea cycle, cells redirect it to the production of pyrimidines, the basic components of DNA and RNA, via a de novo synthetic pathway. The team had previously demonstrated that this pathway is also essential for the growth of cancer cells that are dependent on horizontal mitochondrial transfer.
"When we experimentally blocked de novo pyrimidine synthesis, liver regeneration completely stopped. This proves that this pathway is indispensable and cannot be replaced by rescue mechanisms," says Berwini Endaya, head of the liver regeneration project, in which scientists discovered the key mechanism of the liver.
From toxic compound to essential nutrient
Under normal conditions, ammonia is highly toxic. However, during regeneration, liver tissue converts it into glutamine, which promotes the formation of nucleotides needed for rapid cell division. The study thus reveals a remarkable example of how harmful substances become a vital growth factor under specific physiological conditions.
"This discovery highlights the remarkable metabolic flexibility of the liver. It is able to convert ammonia, which is normally a toxic waste product, into a substance that is key to regeneration," adds Jiří Neužil.
Scientists from the US, Portugal, Korea, and New Zealand participated in the work, underscoring the global reach of this collaboration. Beyond liver biology, this discovery provides new insights into the metabolism of tumors, which often use similar metabolic switches to promote rapid growth.
Link to the publication:
Endaya, B.B., Kučera, L., Le, DD.T. et al. Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation. Nat Commun 16, 9664 (2025). https://doi.org/10.1038/s41467-025-65451-2
Contact:
Prof. Jiří Neužil
Institute of Biotechnology, Czech Academy of Sciences
jiri.neuzil@ibt.cas.cz
+420 723 147 540
Berwini Endaya, Ph.D.
Institute of Biotechnology, Czech Academy of Sciences
berwini.endaya@ibt.cas.cz
+420 777 270 069
(English only)
Title image: Freepik.com
