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However, the development of chemotherapy resistance remains a major obstacle to effective treatment, leading to poor prognosis in these patients. Increasing evidence suggests that metabolic alterations play crucial roles in mediating chemoresistance. Here we investigate the effects of methylmalonic acid (MMA), a mitochondrial\u2010derived metabolite, on GC progression and oxaliplatin resistance. Analysis of clinical samples revealed that elevated serum MMA levels correlated with chemoresistance and advanced tumor stage in GC patients. Functional assays identified that MMA promoted GC cell proliferation, migration, and resistance to oxaliplatin by attenuating DNA damage. Mechanistically, MMA suppressed oxaliplatin\u2010induced \u03b3H2AX expression while upregulating ATAD5 and activating the ATM\/ATR\u2010mediated homologous recombination (HR) repair pathway. In\u00a0vivo studies further confirmed that MMA impaired the antitumor efficacy of oxaliplatin, while silencing PCCA, a key enzyme in MMA synthesis, or supplementing vitamin B12, a regulator of MMA metabolism, reversed MMA\u2010induced chemoresistance. These findings highlight MMA as a potential indicator for oxaliplatin resistance and a therapeutic target in GC. Therefore, targeting MMA through vitamin B12 supplementation could serve as a promising therapeutic strategy to overcome chemoresistance in GC patients with elevated MMA levels.<\/jats:p>","DOI":"10.1096\/fj.202600528r","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:50:57Z","timestamp":1791355857000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Methylmalonic Acid Induces Oxaliplatin Resistance Through Promoting DNA Damage Repair via the ATM\/ATR Pathway in Gastric Cancer"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-4525","authenticated-orcid":false,"given":"Kai","family":"Weng","sequence":"first","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV Peking University Cancer Hospital &amp; Institute  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1628-9748","authenticated-orcid":false,"given":"Jiangbo","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV Peking University Cancer Hospital &amp; 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