APOL2 Stabilizes Ku80 to Confer NHEJ‐Mediated Radioresistance in Gastric Cancer

Abstract Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non‐homologous end joining (NHEJ)‐mediated double‐strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7‐mediated deubiquitylation, thereby increasing Ku80 protein levels to promote NHEJ repair, ultimately conferring radioresistance. Moreover, high‐throughput screening identified formononetin (FN) as a small molecule capable of disrupting the APOL2‐Ku80 interaction, thereby restoring radiosensitivity in GC cells. Our findings underscore the role of APOL2 in mediating radioresistance through Ku80 stabilization and highlight FN as a potential therapeutic agent to counteract radioresistance in GC treatment.