Hepatocellular carcinoma (HCC) remains a global public crisis, with high morbidity and mortality rates and significant limitations in current therapeutic strategies. Metabolic reprogramming serves as a vital energy source and underlying driver of tumor progression. This review aims to systematically summarize the molecular mechanisms of amino acid metabolic reprogramming in HCC, highlight therapeutic targets and biomarkers, and explore potential clinical translation strategies. We first describe the abnormal characteristics of amino acid metabolism in HCC, including glutamine (Gln), branched-chain amino acids (BCAAs), arginine (Arg), serine (Ser), glycine (Gly), and tryptophan (Trp). Glutamine serves as a critical nurient for HCC cells. Glutaminase (GLS) catalyzes its catabolism, supports cellular biosynthesis, and promotes HCC progression. Glutamate-oxaloacetate transaminase (GOT) is involved in Gln metabolism, enhancing cancer cells’ resistance to ferroptosis induced by glutamine deprivation and to damage caused by reactive oxygen species (ROS). BCAAs accumulate in HCC tissues due to impaired catabolic pathways, activating the mTORC1 signaling pathway to promote proliferation. Arg metabolism is regulated by enzymes such as argininosuccinate synthetase 1 (ASS1) and argininosuccinatelyase (ASL), thereby promoting tumorigenesis and metastasis. Additionally, Ser, Gly biosynthesis and Trp catabolism are reprogrammed to support tumor growth and immune escape. In addition, the molecular regulation of these metabolic abnormalities involves amino acid transporters (e.g., SLC7A5, SLC1A5), upstream regulators (e.g., c-Myc, mTORC1, p53), and non-coding RNAs, which synergistically modulate amino acid uptake, metabolism, and signaling transduction. Metabolites such as α-KG, pyruvate (Pyr) and glutathione (GSH) further participate in pathway crosstalk and maintain redox homeostasis. Subsequently, the mechanisms by which amino acid metabolic reprogramming drives HCC progression are clarified. HCC cells modulates the tumor microenvironment by competing for nutrients with immune cells (e.g., depleting Gln to suppress T cell function) and promoting the formation of immunosuppressive phenotypes to facilitate tumor immune escape. It also regulates endothelial cells and cancer-associated fibroblasts to enhance angiogenesis and extracellular matrix remodeling. Moreover, crosstalk between metabolism and epigenetics (e.g., SAM-mediated DNA methylation, succinylation modification) further amplifies tumorigenic signals. We then summarizes promising therapeutic strategies targeting amino acid metabolism. These strategies include developing drugs against metabolic enzymes (e.g., GLS1 inhibitor CB-839, MAT2A inhibitor FIDAS-5), using arginine degrading agents (e.g., Peg-rhArg1, ADI-PEG 20), implementing methionine (Met) restriction therapy, and exploring immune combination therapies (e.g., IDO1 inhibitor combined with anti-PD-1, targeting the DLAT-AUH axis). Besides, the single-target therapies may be limited by metabolic network plasticity and compensatory mechanisms, highlighting the need for combined strategies targeting multiple metabolic nodes. Finally, we point out current challenges and future directions. The existing biomarkers lack sufficient validation, and the spatiotemporal heterogeneity of amino acid metabolism, as well as its crosstalk with lipid and glucose metabolism, remain relatively under-explored. Future research should leverage multi-omics technologies and advanced models (e.g., PDO) to validate metabolic biomarkers. Also, in-depth investigation of the interaction between metabolism and the immune microenvironment should be further explored. Understanding these mechanisms through systematic research could improve treatment precision and efficacy and optimize combined therapeutic strategies.
LI et al. (Thu,) studied this question.