Research advances on amino acid starvation interventions for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive malignancy associated with high mortality. Numerous endeavors have been undertaken to develop more effective pharmaceutical interventions. Metabolic reprogramming is recognized as a hallmark of cancer for adapting to heightened bioenergetic and biosynthetic demands. Amino acid (AA) metabolism dysregulation plays a crucial role in the tumor initiation and progression of HCC, resulting in high reliance on AA availability. This makes HCC cells vulnerable to AA starvation, implying that restricting AA supply and utilization may offer a promising nutritional strategy in HCC therapy. We delineate the pivotal physiological functions and aberrant alterations of various AA metabolisms in HCC. We systematically summarize the recent advances in agents, targets, antineoplastic effects, and mechanisms of various AA starvation strategies in HCC, including dietary restriction, circulating depletion, transporter blockade, and metabolic enzyme inhibition. We further discussed a suite of adaptive responses that enable HCC cells to survive with AA shortage. Targeting these adaptive pathways in combination with AA starvation may enhance the efficacy of HCC treatment. This review aims to provide a comprehensive overview of progress in the field of AA starvation for HCC therapy and to explore novel therapeutic opportunities and strategies through nutritional intervention for HCC therapy.