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O\u2010GlcNAc transferase (OGT) and O\u2010linked \u03b2\u2010N\u2010acetylglucosamine modification (O\u2010GlcNAcylation) are frequently elevated in cancers, yet their specific role in GC chemotherapy remains poorly defined. Contrary to its typical oncogenic function, this study demonstrates that low OGT\/O\u2010GlcNAcylation is associated with resistance to 5\u2010fluorouracil (5\u2010FU) or oxaliplatin (OXA) in GC. Clinically, high OGT expression correlates with better prognosis in patients receiving fluoropyrimidine\/platinum chemotherapy. Functionally, OGT knockdown or O\u2010GlcNAcylation inhibition promotes chemoresistance both in vitro and in vivo. Mechanistically, OGT interacts with and O\u2010GlcNAcylates synaptosomal\u2010associated protein 29 (SNAP29) at Ser\n                    <jats:sup>2<\/jats:sup>\n                    , Ser\n                    <jats:sup>61<\/jats:sup>\n                    , Thr\n                    <jats:sup>130<\/jats:sup>\n                    , and Ser\n                    <jats:sup>153<\/jats:sup>\n                    . This modification inhibits STX17\u2010SNAP29\u2010VAMP8 complex assembly and autophagosome maturation. Molecular dynamics simulations suggest this involves disruption of inter\u2010chain hydrogen bonds and increased flexibility at SNAP29 termini. Loss of SNAP29 O\u2010GlcNAcylation relieves this suppression, enhances protective autophagy, and drives chemoresistance. Additionally, acute 5\u2010FU or OXA treatment downregulates OGT and O\u2010GlcNAcylation, potentially initiating a feedforward resistance loop. Importantly, elevating O\u2010GlcNAcylation with Thiamet\u2010G sensitizes GC tumors to chemotherapy in vivo. These findings reveal a context\u2010dependent role for the OGT\/SNAP29 axis in regulating chemoresistance via autophagy and nominate OGT as a promising therapeutic target in GC.\n                  <\/jats:p>","DOI":"10.1002\/advs.76730","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:48:48Z","timestamp":1784807328000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["O\u2010GlcNAcylation Regulation of SNAP29\u2010Dependent Autophagy Activation Dictates Chemoresistance in Gastric Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Liang","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou Guangdong People's Republic of 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