背景：甲状腺癌（TC）是一种常见的内分泌癌症，预后良好。然而，TC去分化导致的患者预后不良正成为一个紧迫的挑战。近年来，甲基转移酶样3（METTL3）介导的N6-甲基腺苷（m6A）修饰已被证明在多种癌症的发生和进展中发挥重要作用，并在TC中发挥抑癌作用。然而，METTL3在TC中的作用机制仍不清楚。方法：采用免疫组织化学方法评估METTL3与TC患者预后的相关性。使用Mettl3fl/flBrafV600ETPO-cre TC小鼠模型和RNA-seq研究潜在的分子机制，并通过体外实验进一步验证。鉴定了METTL3的靶基因，描述了完整的m6A修饰过程。通过鉴定调节 METTL3 的 miRNA 来解释 TC 中 METTL3 低表达的现象。结果：我们观察到 METTL3 表达与 TC 中的肿瘤进展和不良预后呈负相关。从机制上讲，沉默 METTL3 在体内和体外均促进甲状腺乳头状癌 (PTC) 的进展和去分化。此外，过度表达METTL3可促进PTC和未分化甲状腺癌（ATC）细胞对化疗药物和碘131（131I）给药的敏感性。总体而言，METTL3/PAX8/YTHDC1 轴已被证明在抑制肿瘤发生中发挥着关键作用，并被 miR-493-5p 拮抗。© 作者。

Background: Thyroid cancer (TC) is a common endocrine cancer with a favourable prognosis. However, poor patient prognosis due to TC dedifferentiation is becoming an urgent challenge. Recently, methyltransferase-like 3 (METTL3)-mediated N6 -methyladenosine (m6A) modification has been demonstrated to play an important role in the occurrence and progression of various cancers and a tumour suppressor role in TC. However, the mechanism of METTL3 in TC remains unclear. Methods: The correlation between METTL3 and prognosis in TC patients was evaluated by immunohistochemistry. Mettl3fl/flBrafV600ETPO-cre TC mouse models and RNA-seq were used to investigate the underlying molecular mechanism, which was further validated by in vitro experiments. The target gene of METTL3 was identified, and the complete m6A modification process was described. The phenomenon of low expression of METTL3 in TC was explained by identifying miRNAs that regulate METTL3. Results: We observed that METTL3 expression was negatively associated with tumour progression and poor prognosis in TC. Mechanistically, silencing METTL3 promoted the progression and dedifferentiation of papillary thyroid carcinoma (PTC) both in vivo and in vitro. Moreover, overexpressing METTL3 promoted the sensitivity of PTC and anaplastic thyroid cancer (ATC) cells to chemotherapeutic drugs and iodine-131 (131I) administration. Overall, the METTL3/PAX8/YTHDC1 axis has been revealed to play a pivotal role in repressing tumour occurrence, and is antagonized by miR-493-5p.© The author(s).