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Gestational diabetes mellitus (GDM) is a common metabolic disorder that affects maternal and fetal health. O-GlcNAcylation is increased in GDM and disrupts placental homeostasis. This study aimed to explore the role of O-GlcNAcylation in GDM progression and the underlying mechanism. Trophoblast cell line (HTR-8/SVneo) was treated with high glucose (HG) to assess a cell model. Ferroptosis was evaluated by lipid reactive oxygen species (ROS), malondialdehyde, Fe2+, and glutathione concentrations. The GDM mouse model was established, and blood glucose and blood lipid were measured. The effect of OGT on ELP3 O-GlcNAcylation was measured using immunoprecipitation and western blotting. The results showed that ferroptosis was involved in HG-induced cell injury, and OGT expression was increased in these cells (over 3-fold). Knockdown of OGT inhibited HG-induced ferroptosis in vitro (P < 0.01), and reduced blood glucose (P < 0.01), blood lipid (P < 0.01), and ferroptosis (P < 0.01) in GDM mice. Moreover, silencing of OGT reduced ELP3 protein stability (P < 0.01) via inhibiting ELP3 O-GlcNAcylation at Ser408 site. Overexpression of ELP3 abrogated the inhibition of ferroptosis in HG-induced cells caused by OGT knockdown (P < 0.01). In conclusion, silencing of OGT inhibits trophoblast ferroptosis by suppressing O-GlcNAcylation of ELP3, thereby ameliorating GDM. The findings suggest that targeting OGT-mediated O-GlcNAcylation may be a promising strategy for GDM treatment.