N-methylguanosine tRNA modification promotes gastric cancer progression by activating SDHAF4-dependent mitochondrial oxidative phosphorylation.

N-methylguanosine (mG) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of mG tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated mG tRNA modifications in promoting GC progression. Upregulation of mG methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression in vitro and in vivo. Mechanistically, METTL1 knockdown reduces the expression of mG-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated mG tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.