Gao Benjian, Zheng Dongning, Liu Hong, Guo Yu, Ye Yuntao, Chen Zhou, Yang Fengyi, Liu Jie, Zhang Guangnian, Feng Guoying, Liu Yongfa, Wang Qiang, Su Song, Yang Xiaoli, Li Bo
Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Hepatobiliary Surgery, Dazhou Central Hospital, Dazhou, China.
Redox Biol. 2025 Aug 5;86:103813. doi: 10.1016/j.redox.2025.103813.
Glutamine addiction represents a metabolic vulnerability in hepatocellular carcinoma (HCC), making glutaminase inhibitor CB-839 therapy a promising approach. However, effective therapeutic strategies are not yet available. In this study, we aim to investigate the potential role of asparagine synthetase (ASNS) as a target for HCC therapy during CB-839 treatment. CB-839 suppressed HCC cell growth, triggered apoptosis, and induced oxidative stress along with the disruption of amino acid metabolism. Moreover, ASNS was induced by CB-839 treatment through the activation of the amino acid response pathway. ASNS was significantly upregulated in HCC tumor tissues and was positively associated with poor prognosis; indeed our results revealed that its overexpression facilitated the proliferation, migration, and invasion of HCC cells. Furthermore, ASNS increased glutaminolysis and glutathione synthesis through reprogramming glutamine metabolism to maintain intracellular redox homeostasis, thereby activating the mTOR pathway that contributed to HCC progression. ASNS knockdown sensitized HCC cells to CB-839 both in vitro and in vivo. Overall, ASNS modulated the sensitivity to CB-839 in HCC through metabolic reprogramming, potentially serving as a biomarker for CB-839 response and a promising therapeutic target for HCC.
谷氨酰胺成瘾代表了肝细胞癌（HCC）中的一种代谢脆弱性，这使得谷氨酰胺酶抑制剂CB - 839疗法成为一种有前景的方法。然而，目前尚未有有效的治疗策略。在本研究中，我们旨在探讨天冬酰胺合成酶（ASNS）在CB - 839治疗期间作为HCC治疗靶点的潜在作用。CB - 839抑制HCC细胞生长，引发细胞凋亡，并诱导氧化应激以及氨基酸代谢紊乱。此外，CB - 839处理通过激活氨基酸反应途径诱导ASNS表达。ASNS在HCC肿瘤组织中显著上调，且与预后不良呈正相关；事实上，我们的结果表明其过表达促进了HCC细胞的增殖、迁移和侵袭。此外，ASNS通过重新编程谷氨酰胺代谢增加谷氨酰胺分解和谷胱甘肽合成，以维持细胞内氧化还原稳态，从而激活促进HCC进展的mTOR途径。ASNS敲低在体外和体内均使HCC细胞对CB - 839敏感。总体而言，ASNS通过代谢重编程调节HCC对CB - 839的敏感性，可能作为CB - 839反应的生物标志物以及HCC的一个有前景的治疗靶点。
