USP2 Promotes Nasopharyngeal Carcinoma Progression by Activating TRAF2/NF‐κB Signaling and Stabilizing MMP2

A methylation and mRNA levels in metastatic NPC. Validation employed qPCR, Western blot, and immunohistochemistry in clinical samples and NPC cell lines. Functional assays included CCK-8, flow cytometry, Transwell, wound healing, and mechanistic studies such as cyclohexane chase, co-immunoprecipitation, ubiquitination assays were performed under USP2 knockdown/overexpression and NF-κB inhibition. Our results showed that USP2 was significantly upregulated in metastatic NPC tissues and cell lines. USP2 knockdown suppressed proliferation, migration, and invasion, induced apoptosis, and attenuated NF-κB activation by reducing nuclear p65 and TRAF2/MMP2 expression. Conversely, USP2 overexpression enhanced malignancy, which was reversed by NF-κB inhibition. Critically, USP2 directly bound MMP2, extended its protein half-life, and reduced K48-linked polyubiquitination. In conclusion, USP2 drives NPC migration and invasion by activating TRAF2-dependent NF-κB signaling and directly mediating K48-linked deubiquitination of MMP2, dually enhancing MMP2 expression. Targeting the USP2-MMP2 axis may offer a novel therapeutic strategy to impede NPC dissemination, addressing an unmet clinical need in advanced disease.