Abstract

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with poor outcomes at advanced stages. Although ubiquitination is critical in regulating oncogenic pathways, the role of many ubiquitin-specific proteases (USPs) in NPC remains unexplored. In this study, we conducted a systematic screen of USPs to identify regulators of ULK1, a key initiator of autophagy and oncogene in NPC. We identified USP54 as a potent stabilizer of ULK1. Bioinformatic analyses of NPC transcriptomic datasets revealed that both ULK1 and USP54 are significantly overexpressed in NPC tissues. Functional assays demonstrated that USP54 overexpression enhanced NPC cell viability, colony formation, migration, and invasion by promoting autophagy, independently of PI3K/AKT pathway activity. Importantly, pharmacological inhibition of autophagy or genetic silencing of ULK1 abolished the oncogenic effects of USP54, indicating that ULK1-dependent autophagy mediates USP54-driven NPC progression. Our findings revealed that USP54 may promote autophagy and malignancy in NPC via regulating ULK1 stability, highlighting USP54 as a potential therapeutic target for NPC treatment.