Metabolic reprogramming is a critical driver in the pathogenesis of gastric cancer (GC). However, the intricate regulatory mechanisms that govern this reprogramming and their role in GC progression remain inadequately understood. Here, we have elucidated that Methyltransferase-like 10 (METTL10) is a pivotal regulator of gastric tumorigenesis, significantly enhancing purine metabolism in GC cells. Mechanistically, METTL10 methylates and competes with the protein inhibitor of activated STAT3 (PIAS3) for binding to microphthalmia-associated transcription factor (MITF), thereby reducing the sumoylation and ubiquitination of MITF and subsequently activating purine metabolism. Moreover, the oncogenic effects of METTL10 in gastric tumorigenesis are contingent upon MITF and the methylation of lysine 442 in PIAS3, both of which are strongly correlated with poor clinical features. Additionally, we identified a compound, LZQ-02-023-01, which effectively mitigates the oncogenic activity of METTL10 in GC. These findings suggest that METTL10 is involved in purine metabolism reprogram to promote gastric cancer. These findings underscored METTL10's critical role in the metabolic reprogramming of purine metabolism and highlight its potential as a therapeutic target in the treatment of GC.