A novel small-molecule inhibitor GSK-F1 confers radiosensitivity by inhibiting the NSUN2/TP53/RAD51 axis-mediated DNA homologous recombination repair in nasopharyngeal carcinoma

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), yet radioresistance frequently develops and leads to the failure of treatment for NPC. NSUN2 acts as a potential oncogene in NPC, but its role in NPC radioresistance remains unclear. In this study, we revealed that NSUN2 was upregulated in radioresistant NPC tissues. Through a series of functional assays following radiotherapy, including CCK-8, colony formation, apoptosis analysis by flow cytometry, we demonstrated that NSUN2 promoted radioresistance and enhanced DNA damage repair in NPC cells. Mechanistically, NSUN2 negatively regulated TP53 expression and competitively enhanced the UCHL3-RAD51 interaction, thereby facilitating RAD51 deubiquitination and RAD51-mediated homologous recombination repair of DNA double-strand breaks. Moreover, the suppressive effect of NSUN2 knockdown on NPC radioresistance was reversed by TP53 knockdown. Furthermore, the small molecule GSK-F1 was found to directly bind to NSUN2 and promote its proteasomal degradation, consequently activating the downstream TP53/RAD51 signaling axis and increasing NPC cell cytotoxicity and radiosensitivity. In conclusion, our study elucidates that NSUN2 promotes NPC radioresistance by negatively regulating the TP53/RAD51 axis, and the NSUN2 inhibitor GSK-F1 functions as a radiosensitizer in NPC by disrupting the NSUN2/TP53/RAD51 signaling pathway, thereby providing a potential clinical strategy for the targeted therapy and radiosensitivity in NPC.