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Lymph node migration results in poor prognoses for nasopharyngeal carcinoma (NPC) patients. Tricetin, a flavonoid derivative, regulates tumorigenesis activity through its antiproliferative and antimetastatic properties. However, the molecular mechanism of tricetin affecting the migration and invasion of NPC cells remains poorly understood. In this paper, we examined the antimetastatic properties of tricetin in human NPC cells. Our results demonstrated that tricetin at noncytotoxic concentrations (0–80 3M) noticeably reduced the migration and invasion of NPC cells (HONE-1, NPC-39, and NPC-BM). Moreover, tricetin suppressed the indicative protease, presenilin-1 (PS-1), as indicated by protease array. PS-1 was transcriptionally inhibited via the Akt signaling pathway but not mitogen-activated protein kinase pathways, such as the JNK, p38, and ERK1/2 pathways. In addition to upregulating GSK-3 β phosphorylation through Akt suppression, tricetin may downregulate the activity of PS-1. Overall, our study provides new insight into the role of tricetin-induced molecular regulation in the suppression of NPC metastasis and suggests that tricetin has prospective therapeutic applications for patients with NPC. [ABSTRACT FROM AUTHOR]