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This study identifies AOC3 downregulation as a critical contributor to IM resistance. Analyzing clinical samples and IM\u2010sensitive\/resistant GIST cell lines, we found AOC3 significantly decreased in resistant states. Functionally, AOC3 knockdown promoted IM resistance, enhanced glycolytic activity, and increased lactate production. Mechanistically, AOC3 loss attenuated ubiquitin\u2010mediated degradation of HK2, stabilizing this glycolytic enzyme and boosting lactate generation. Subsequent histone lactylation, notably at H3K18, enriched at the Myc promoter and stimulated its transcription. Crucially, HK2 overexpression reversed AOC3's suppressive effects on glycolysis, lactylation, Myc expression, and IM resistance. In vivo xenograft models confirmed these findings. We conclude that AOC3 acts as a tumor suppressor by promoting HK2 degradation; its loss triggers a HK2\/glycolysis\/lactylation\/Myc axis driving IM resistance, positioning AOC3 as a promising prognostic biomarker and therapeutic target in GIST.<\/jats:p>","DOI":"10.1002\/mc.70084","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T19:21:16Z","timestamp":1769109676000},"page":"407-421","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AOC3 Loss Promotes Imatinib Resistance in GIST by Stabilizing HK2 and Enhancing H3K18la\u2010Driven Myc Transcription"],"prefix":"10.1002","volume":"65","author":[{"given":"Zhiyuan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou Jiangsu China"},{"name":"Department of General Surgery The First People's Hospital of Yancheng The Yancheng Clinical College 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