The role of the CTBP2 mediated glycolytic pathway in nasopharyngeal carcinoma metastasis.

Nasopharyngeal carcinoma (NPC) progression is closely linked to aerobic glycolysis. C-terminal binding protein 2 (CTBP2), recognized as a glycolytic sensor, supporting the metabolic and biosynthetic needs of cancer cells and driving tumor progression and metastasis. However, its role in NPC metastasis remains poorly defined. Herein, we performed immunohistochemical analyses of CTBP2 and Zinc finger E-box-binding homeobox 1(ZEB1) expression in primary NPC tissues, NPC lymph-node metastatic tissues, and paracancerous tissues. Both CTBP2 and ZEB1 were markedly upregulated in NPC and metastatic tissues, with CTBP2 expression significantly correlated with TNM stage progression. We constructed CTBP2 knockdown and ZEB1 overexpression vectors, transfected them into HNE-1 NPC cells, and further validated their effects in a xenograft model established in BALB/c nude mice. We identified that CTBP2 silencing suppressed ZEB1 mRNA expression and glycolytic activity, and markedly inhibited EMT, proliferation, invasion, and metastatic potential of NPC cells. Conversely, ZEB1 overexpression restored the proliferative and migratory capacities of CTBP2-silenced cells. Dual-luciferase reporter assays further indicated that ZEB1 transcriptionally activates HK2, thereby enhancing glycolysis. This study is the first to reveal that the CTBP2/ZEB1/HK2 axis drives NPC progression by coupling glycolytic regulation with EMT and metastasis. These findings uncover a critical metabolic signaling cascade in NPC progression and identify promising targets for therapeutic development and warrant further investigation as potential treatments for NPC.