Nasopharyngeal carcinoma (NPC) is a common malignancy in certain geographic regions, with radiotherapy serving as the primary treatment. Recent research shows that epigenetics and deubiquitinases (DUBs) are crucial in NPC progression and treatment response. However, the emergence of radioresistance in NPC cells presents a significant challenge, often resulting in treatment failure. This study focuses on understanding the role of OTUD1 and methylation in NPC radiosensitivity and their mechanisms. In this study, OTUD1 and TFAP2C expression were significantly reduced in radioresistant NPC cell lines, likely due to the high methylation of TFAP2C. OTUD1 is significantly downregulated in radioresistant NPC, and its low expression is associated with enhanced radioresistance both in vitro and in vivo. Mechanistically, OTUD1 enhances NPC radiosensitivity by deubiquitinating and stabilizing SLC25A11, leading to increased Reactive oxygen species (ROS) and apoptosis. Clinically, low OTUD1 and SLC25A11 expression is associated with poor radiotherapy response and survival outcomes. Furthermore, we demonstrate that combining the methylation inhibitor Decitabine (DAC) with radiotherapy significantly improves treatment efficacy by overcoming radioresistance. These findings provide insights into NPC radioresistance and suggest that using DAC in combination with radiotherapy to target the TFAP2C-OTUD1-SLC25A11 axis could be a promising strategy to overcome radioresistance.