biostudies-literatureZu DNatural Science Foundation of Zhejiang ProvinceNatural Science Foundation of ChinaNational Natural Science Foundation of ChinaZhejiang Medical and Health Science and Technology ProgramBeijing Science and Technology Innovation Medical Development FoundationKey Laboratory of Prevention, Diagnosis, and Therapy of Upper Gastrointestinal Cancer of Zhejiang Provincee06294https://www.ebi.ac.uk/biostudies/studies/S-EPMC12667481biostudies-literatureUnknown12(44)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 cAdvanced science (Weinheim, Baden-Wurttemberg, Germany)APOL2 Stabilizes Ku80 to Confer NHEJ-Mediated Radioresistance in Gastric Cancer.PMC1266748132370797KC2023-JX-0270-0782473195LTGY23H1600182024KY7892022E10021Liu HJing JHu YLiu MHe HGuan FLuo GDu YZhong YDeng MCheng XBao QShi YYe ZLiang CLi XHuang YHe YZu DTainer JAXu SBacolla AZhang CWu WfalseAPOL2 Stabilizes Ku80 to Confer NHEJ-Mediated Radioresistance in Gastric Cancer.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 c2025-01-01T00:00:00Z2025 Nov2026-06-05T20:43:42.388Z2026-05-21T03:13:06.621ZS-EPMC126674814095333110.1002/advs.202506294