Stabilization of VDAC1 by USP10 facilitates radioresistance and metastasis in nasopharyngeal carcinoma via MTOR-dependent autophagy pathway: an experimental study

Background: Radioresistance represents a major obstacle in the treatment of nasopharyngeal carcinoma (NPC), often leading to tumor recurrence and metastasis. Although autophagy is a critical regulatory process in cancer biology, its specific role in NPC radioresistance remains poorly understood. Method: We integrated machine learning, weighted gene co-expression network analysis (WGCNA), and differential gene expression (DEG) analysis to identify potential oncogenes using datasets from the Gene Expression Omnibus (GEO). The role of the hub gene voltage-dependent anion channel l (VDAC1) in radioresistance and tumor progression was evaluated through in vitro and in vivo functional assays. The association between VDAC1 and the tumor immune microenvironment was assessed using the CIBERSORT algorithm. Further mechanistic insights were gained through co-immunoprecipitation (Co-IP), immunofluorescence, and mass spectrometry (MS). Results: VDAC1, an autophagy-related gene, was overexpressed in NPC and correlated with radioresistance and metastasis. Knockdown of VDAC1 significantly suppressed radioresistance and metastatic potential both in vitro and in vivo . Mechanistically, USP10—a deubiquitinase upregulated in NPC—was found to bind to and deubiquitinate VDAC1 at lysine 161, thereby preventing its proteasomal degradation. Stabilization of VDAC1 by USP10 activated mTOR-mediated autophagy, promoting NPC progression. Conclusions: Our findings suggest that VDAC1 may represent a promising therapeutic target for overcoming radioresistance in NPC.