Methylmalonic Acid Induces Oxaliplatin Resistance Through Promoting DNA Damage Repair via the ATM/ATR Pathway in Gastric Cancer

ABSTRACT Surgical intervention and chemotherapy have enhanced the survival rates of patients with advanced gastric cancer. 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‐derived 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‐induced γH2AX expression while upregulating ATAD5 and activating the ATM/ATR‐mediated homologous recombination (HR) repair pathway. In vivo 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‐induced 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.