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14 reviewsN7-methylguanosine (m7G) modification of transfer RNA (tRNA) is essential for the biological functions of tRNAs and has beenfound to play a regulatory role in a variety of human cancers. However, the biological function of METTL1-mediated m7G tRNAmodification in papillary thyroid cancer (PTC) is unclear. Here, we found that METTL1 is significantly upregulated in PTC tissuescompared to normal control tissues and is associated with poor PTC prognosis. Functional analysis confirmed that METTL11234567890();,:promotes the proliferation and metastasis of PTC cells in a manner dependent on its tRNA methyltransferase activity.Mechanistically, METTL1 knockdown leads to a decrease in the abundance of certain m7G-modified tRNAs, which suppresses them7G tRNA modification-mediated codon-specific translation of TNF-α. Furthermore, exogenous supplementation with TNF-αpartially reversed the decrease in the proliferation and metastasis of PTC cells induced by METTL1 deletion. Positive correlationsbetween METTL1, WDR4, and TNF-α expression, which affect the proliferation and metastasis of PTC, were confirmed via analysis ofmicroarrays containing PTC tissues. These results demonstrate the oncogenic role of METTL1-mediated m7G tRNA modification inregulating codon-specific translation efficiency in PTC and suggest that targeting METTL1 may be a promising therapeuticapproach for overcoming PTC progression by inhibiting PTC cell proliferation and metastasis.Cell Death and Disease (2025) 16:378 ;