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

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.