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Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review)

  • Authors:
    • Boying Zhu
    • Chaoyang Wang
    • Peng Liu
    • Zhifeng Qu
    • Ran Qi
    • Shengjiang Chen
    • Huanzhang Niu
  • View Affiliations / Copyright

    Affiliations: Department of Ultrasound, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Interventional Radiology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Endocrinology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Radiation Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 215
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    Published online on: June 8, 2026
       https://doi.org/10.3892/ijmm.2026.5886
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Abstract

Non‑alcoholic fatty liver disease (NAFLD) and its advanced form, non‑alcoholic steatohepatitis (NASH), are now leading causes of chronic liver disease worldwide. Recent evidence highlights the central role of urea cycle and arginine metabolism dysregulation in NAFLD/NASH pathogenesis. Downregulation of key urea cycle enzymes, such as carbamoyl phosphate synthetase 1, ornithine transcarbamylase and argininosuccinate synthase, impairs ammonia detoxification, leading to hyperammonemia, mitochondrial dysfunction and oxidative stress. Epigenetic modifications, notably DNA methylation and histone changes, contribute to this metabolic reprogramming. Aberrant arginine metabolism, particularly the imbalance between urea and nitric oxide (NO) pathways, exacerbates liver inflammation and fibrosis through increased inducible nitric oxide synthase (NOS) activity in macrophages and hepatic stellate cells, driving excessive NO and polyamine production. In contrast, physiological NO signaling via endothelial NOS supports mitochondrial health and metabolic homeostasis. Clinically, urea cycle and arginine metabolites, including blood ammonia and urea cycle metabolites, serve as potential biomarkers for disease severity. Restoring urea cycle function and rebalancing arginine‑NO metabolism through targeted interventions, such as citrulline/arginine supplementation or enzyme modulation, are promising strategies. 
View Figures

Figure 1

Simplified schematic of the
hepatocyte urea cycle and L-arginine network. In mitochondria,
NAGS, CPS1 and OTC convert NH3 to citrulline, which in
the cytosol is processed by ASS1 and ASL into arginine and
fumarate. ARG1 then yields urea and regenerates ornithine. All
figures were generated using Microsoft PowerPoint (Microsoft
Corporation). NAGS, N-acetyl-L-glutamate synthase; CPS1, carbamoyl
phosphate synthetase 1; OTC, ornithine transcarbamylase; ASS1,
argininosuccinate synthase; ASL, argininosuccinate lyase; ARG1,
cytosolic arginase 1.

Figure 2

Spatial and cell-type heterogeneity
of hepatic nitrogen metabolism. Hepatocytes are divided into
periportal (zone 1), midzonal (zone 2) and pericentral (zone 3)
regions along oxygen and nutrient gradients. Zone 1 cells express
high levels of urea cycle enzymes to convert portal-vein-derived
NH3 into urea, while residual ammonia reaching zone 3 is
captured by pericentral glutamine synthetase to form glutamine. All
figures were generated using Microsoft PowerPoint (Microsoft
Corporation).

Figure 3

Epigenetic suppression of the
hepatocyte urea cycle under metabolic stress: in highfat,
highcholesterol diet-induced NASH rats, CpG hypermethylation of
CPS1 and OTC promoters leads to a marked drop in their mRNA/protein
levels, reduced enzymatic activity and intrahepatic ammonia
buildup-changes that are partially reversed upon return to a normal
diet. Likewise, human NAFLD (steatosis and NASH) liver samples show
a 30-40% decrease in CPS1, OTC and ASS1 transcripts correlating
with impaired urea production and highfructose, highfat mouse
hepatocytes display similar promoter hypermethylation and enzyme
downregulation. All figures were generated using Microsoft
PowerPoint (Microsoft Corporation). NASH, non-alcoholic
steatohepatitis; CPS1, carbamoyl phosphate synthetase 1; OTC,
ornithine transcarbamylase; NAFLD, non-alcoholic fatty liver
disease; ASS1, argininosuccinate synthase; ECAR, extracellular
acidification rate.

Figure 4

Metabolic reprogramming of hepatic
stellate cells and ornithine-polyamine flux during hepatic
inflammation and NAFLD/NASH. During hepatic inflammation, hepatic
stellate cells are mobilized, their morphology shifts from a
stellate to a flattened shape and the expression of α-SMA, type I
collagen and fibronectin is markedly upregulated. Cellular energy
metabolism is reprogrammed from mitochondrial fatty acid oxidation
toward a phenotype predominantly reliant on aerobic glycolysis and
glutamine metabolism, providing rapid ATP and biosynthetic
intermediates. In activated HSCs, ornithine ODC1 is strongly
upregulated, catalyzing the decarboxylation of ornithine and its
further conversion into the polyamines spermidine and spermine.
Mitochondrial ARG2 is upregulated and hydrolyzes arginine to
ornithine and urea. Regulation by NO and TGF-β increases the
affinity of the HNF-3β binding site within the CPS1 promoter,
maintaining CPS1 at a low-to-intermediate expression level, thereby
sustaining the production of carbamoyl phosphate and NAG and
providing essential intermediates for ARG2-driven ornithine
generation. In the pathological context of NAFLD/NASH, hepatic
expression of CPS1, OTC and ASS1 is reduced, leading to excessive
accumulation of ammonia and arginine. Hepatocyte-derived ornithine
and polyamines (such as spermine) can act on HSCs via receptors
including p75NTR and, through ARG1-mediated pathways, further
promote collagen synthesis, thereby establishing a vicious cycle of
local fibrogenesis. All figures were generated using Microsoft
PowerPoint (Microsoft Corporation). NAFLD, non-alcoholic fatty
liver disease; NASH, non-alcoholic steatohepatitis; α-SMA, α-smooth
muscle actin; HSCs, hepatic stellate cells; ODC1, ornithine
decarboxylase 1; ARG, cytosolic arginase; NO, nitric oxide; CPS1,
carbamoyl phosphate synthetase 1; OTC, ornithine transcarbamylase;
ASS1, argininosuccinate synthase.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu B, Wang C, Liu P, Qu Z, Qi R, Chen S and Niu H: Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review). Int J Mol Med 58: 215, 2026.
APA
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., & Niu, H. (2026). Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review). International Journal of Molecular Medicine, 58, 215. https://doi.org/10.3892/ijmm.2026.5886
MLA
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., Niu, H."Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review)". International Journal of Molecular Medicine 58.2 (2026): 215.
Chicago
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., Niu, H."Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review)". International Journal of Molecular Medicine 58, no. 2 (2026): 215. https://doi.org/10.3892/ijmm.2026.5886
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu B, Wang C, Liu P, Qu Z, Qi R, Chen S and Niu H: Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review). Int J Mol Med 58: 215, 2026.
APA
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., & Niu, H. (2026). Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review). International Journal of Molecular Medicine, 58, 215. https://doi.org/10.3892/ijmm.2026.5886
MLA
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., Niu, H."Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review)". International Journal of Molecular Medicine 58.2 (2026): 215.
Chicago
Zhu, B., Wang, C., Liu, P., Qu, Z., Qi, R., Chen, S., Niu, H."Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review)". International Journal of Molecular Medicine 58, no. 2 (2026): 215. https://doi.org/10.3892/ijmm.2026.5886
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