2. Academic Validation
  3. Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation

Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation

  • Nat Commun. 2025 Nov 4;16(1):9664. doi: 10.1038/s41467-025-65451-2.
Berwini B Endaya # 1 2 3,  Lukáš Kučera # 4,  Dan-Diem Thi Le # 5 6,  Jessica B Spinelli 7,  Andrea Brožková 6,  Dominika Luptáková 8,  Kryštof Klíma 4,  Gabriela L Oliveira 5 9 10 11,  Petra Brisudová 5,  Klára Boháčová 5,  Štěpána Boukalová 5,  Renata Zobalová 5,  František Kolář 12,  Karel Chalupsky 4,  Klára Dohnalová 4,  Arash Yarmohammadi-Barzegar 6,  Šárka Dvořáková 5,  Evgeniya Biryukova 4,  Marta Kaliaeva 4,  Vladimír Havlíček 8 13,  Radislav Sedláček 4,  Jan Procházka 4,  Libor Vítek 14 15,  Sunghyouk Park 16,  Pavel Martásek 14 15,  Zdeněk Krška 14 15,  Paulo J Oliveira 9 10,  Michael V Berridge 17,  Jiří Neužil 18 19 20 21
Affiliations

Affiliations

  • 1 Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic. [email protected].
  • 2 Faculty of Science, Charles University, Prague, Czech Republic. [email protected].
  • 3 First Faculty of Medicine, Charles University, Prague, Czech Republic. [email protected].
  • 4 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
  • 5 Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.
  • 6 Faculty of Science, Charles University, Prague, Czech Republic.
  • 7 Worcester Chan Medical School, University of Massachusetts, Cambridge, MA, USA.
  • 8 Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic.
  • 9 CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
  • 10 CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
  • 11 PDBEB - Doctoral Programme in Experimental Biology and Biomedicine, Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
  • 12 Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
  • 13 Faculty of Science, Palacký University, Olomouc, Czech Republic.
  • 14 First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 15 General University Hospital, Prague, Czech Republic.
  • 16 College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul, Korea.
  • 17 Malaghan Institute of Medical Research, Kelburn, Wellington, New Zealand.
  • 18 Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic. [email protected].
  • 19 Faculty of Science, Charles University, Prague, Czech Republic. [email protected].
  • 20 First Faculty of Medicine, Charles University, Prague, Czech Republic. [email protected].
  • 21 School of Pharmacy and Medical Science, Griffith University, Southport, Qld, Australia. [email protected].
  • # Contributed equally.
PMID: 41188238 DOI: 10.1038/s41467-025-65451-2
Abstract

Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

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