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However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non\u2010homologous end joining (NHEJ)\u2010mediated double\u2010strand 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\u2010mediated deubiquitylation, thereby increasing Ku80 protein levels to promote NHEJ repair, ultimately conferring radioresistance. Moreover, high\u2010throughput screening identified formononetin (FN) as a small molecule capable of disrupting the APOL2\u2010Ku80 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.<\/jats:p>","DOI":"10.1002\/advs.202506294","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T19:59:52Z","timestamp":1757966392000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["APOL2 Stabilizes Ku80 to Confer NHEJ\u2010Mediated Radioresistance in Gastric Cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Dan","family":"Zu","sequence":"first","affiliation":[{"name":"School of Life Sciences Tianjin University  Tianjin 300100 China"},{"name":"Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou 310022 China"},{"name":"Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)  Hangzhou 310022 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