Amino Acid Metabolism in Chronic Liver Disease: from Pathogenic Driver to Therapeutic Target

Amino acid metabolism is central to the liver's multifaceted physiology, serving as the cornerstone for protein homeostasis, metabolic integration, and tissue repair and regeneration. In addition, the dysregulation of amino acid metabolism is intricately linked to the pathogenesis and progression of a wide spectrum of liver diseases, acting as a central pathological driver beyond a passive metabolic consequence. In metabolic dysfunction-associated steatotic liver disease (MASLD), characteristic alterations in circulating branched-chain amino acids (BCAAs) and glycine levels directly promote hepatic steatosis, oxidative stress, and inflammation. The progression to hepatocellular carcinoma (HCC) is fueled by a profound metabolic reprogramming that creates a dependency on amino acids like glutamine and aspartate for energy and biomass, while methionine and tryptophan metabolism foster an immunosuppressive microenvironment and epigenetic dysregulation to facilitate immune evasion and tumor growth. Furthermore, in liver fibrosis and cirrhosis, metabolic adaptations support disease progression, whereas in hepatic encephalopathy, the hallmark imbalance between BCAAs and aromatic amino acids, coupled with ammonia neurotoxicity, disrupts neurotransmitter balance. These disease-specific alterations not only provide robust biomarkers for diagnosis and prognosis but, more importantly, reveal critical therapeutic vulnerabilities. Consequently, targeting amino acid metabolism emerges as a promising strategic avenue, encompassing dietary interventions, targeted supplementation, and pharmacological inhibition for the development of novel therapeutics across the landscape of liver diseases. This review aims to systematically expound on these dual physiological and pathological roles, arguing that such disease-specific metabolic alterations not only provide biomarkers but, more importantly, unveil targetable vulnerabilities, thereby positioning amino acid metabolism as a strategic frontier for developing novel therapeutics across liver diseases.