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METTL14 alleviates pyroptosis of placental trophoblasts in gestational diabetes mellitus through the lncRNA MEG8/WNT7A axis via m6A modification.

Xue-Li Gao·Yun-Tao Wei·Xiao-Yan Yu
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Abstract

Gestational diabetes mellitus (GDM) is a pregnancy complication associated with abnormal placental trophoblast function. Pyroptosis has been implicated in GDM pathogenesis, yet the role of m6A modification in this process remains unclear. We hypothesized that METTL14 regulates trophoblast pyroptosis through m6A-dependent modulation of the lncRNA MEG8/WNT7A axis. This study investigated the mechanism of METTL14 in pyroptosis of placental trophoblasts in GDM. HG-treated HTR8/SVneo cells were used as a cell model. METTL14, WNT7A, and lncRNA MEG8 expression was detected by RT-qPCR and western blot. Placental damage, cell injury, and pyroptosis markers were assessed. YTHDF2-mediated m6A enrichment on lncRNA MEG8, the interaction between lncRNA MEG8 and EZH2, and H3K27me3 enrichment on the WNT7A promoter were analyzed. Results showed that lncRNA MEG8 was upregulated, while METTL14 and WNT7A were downregulated. METTL14 overexpression reduced placental damage and trophoblast pyroptosis. Mechanistically, METTL14 suppressed lncRNA MEG8 expression through YTHDF2-mediated m6A methylation. Reduced lncRNA MEG8 decreased EZH2 recruitment to the WNT7A promoter, lowered H3K27me3 levels, and consequently promoted WNT7A expression. Rescue experiments confirmed that lncRNA MEG8 overexpression or WNT7A knockdown attenuated the suppressive effect of METTL14 on pyroptosis. In conclusion, METTL14 acts as an upstream regulator that inhibits trophoblast pyroptosis and ameliorates GDM-induced damage through the lncRNA MEG8/WNT7A axis via YTHDF2-mediated m6A modification, highlighting METTL14 as a potential therapeutic target.

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HumansFemaleRNA, Long NoncodingPregnancyWnt ProteinsDiabetes, GestationalTrophoblastsPyroptosisMethyltransferasesCell LinePlacentaEpitranscriptomeRNA MethylationAdenosineEnhancer of Zeste Homolog 2 ProteinGestational diabetes mellitusLncRNA MEG8METTL14Placental trophoblastsWNT7AJournal Article

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Xue-Li Gao, Yun-Tao Wei, Xiao-Yan Yu. 2026-09-11. METTL14 alleviates pyroptosis of placental trophoblasts in gestational diabetes mellitus through the lncRNA MEG8/WNT7A axis via m6A modification.. https://doi.org/10.1007/s10142-026-01986-x

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