《生命科学》 2026, 38(1): 118-132

肝细胞癌中氨基酸代谢重编程的研究进展

李尤美¹ , 周新茹¹ , 夏佳佳¹ , 刘 伟^1,2 , 王春玉^1,*

¹中国医科大学生命科学学院，教育部医学细胞生物学重点实验室暨国家卫生健康委细胞生物学重点实 验室，染色质生物学研究室，沈阳 110122 ²中国医科大学附属盛京医院生殖医学中心，沈阳 110004

摘　要：

氨基酸代谢重编程在肝细胞癌（hepatocellular carcinoma，HCC）发生发展中起关键作用。HCC中谷氨酰胺、支链氨基酸、精氨酸等代谢存在异常，关键代谢酶（如GLS1、ASS1）和调控因子（c-Myc、mTORC1）表达失调，驱动肿瘤细胞增殖、侵袭、转移并重塑肿瘤微环境，促进肿瘤免疫逃逸。同时，代谢物（如α-KG、GSH）及表观遗传调控也参与其中。目前，靶向代谢酶药物开发（如GLS1抑制剂、ARG）、Met限制疗法及氨基酸代谢酶免疫联合治疗（IDO抑制剂、靶向DLAT-AUH轴）展现出治疗潜力。本文阐述了HCC中氨基酸代谢的作用机制及相关靶向治疗策略研究进展。

通讯作者：王春玉 , Email:cywang@cmu.edu.cn

Research progress on amino acid metabolic reprogramming in hepatocellular carcinoma

LI You-Mei¹ , ZHOU Xin-Ru¹ , XIA Jia-Jia¹ , LIU Wei^1,2 , WANG Chun-Yu^1,*

¹Chromatin Biology Laboratory, Key Laboratory of Medical Cell Biology Ministry of Education, Key laboratory of Cell Biology Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang 110122, China ²Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China

Abstract:

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.

Communication Author：WANG Chun-Yu , Email:cywang@cmu.edu.cn