METTL10‐Mediated PIAS3 Methylation Links Purine Metabolism to Gastric Cancer Progression

Abstract Metabolic dysregulation plays a significant role in the development of gastric cancer (GC). However, the mechanisms that control this change and its impact on GC progression remain poorly understood. In this study, it is demonstrated that methyltransferase‐like 10 (METTL10) is a key regulator of gastric tumor formation by enhancing purine metabolism in GC cells. It is discovered that METTL10 methylates the protein inhibitor of activated STAT3 (PIAS3) at the lysine 442 (K442) residue, which interferes with the interaction of PIAS3 with microphthalmia‐associated transcription factor (MITF). As a result, the sumoylation and ubiquitination of MITF by PIAS3 are reduced, leading to MITF stabilization and activation of purine metabolism. Importantly, both the accumulation of MITF and the methylation of K442 in PIAS3 are required for the oncogenic effects of METTL10, and both factors are closely linked to poor clinical outcomes in GC. Furthermore, this study identified a compound, LZQ‐02‐023‐01, which effectively induces the METTL10‐mediated ubiquitination and degradation of MITF, thereby reducing the oncogenic activity of METTL10. The findings suggest that METTL10 plays an important role in reprogramming purine metabolism, which promotes GC, highlighting it as a potential therapeutic target for GC treatment.