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Metformin and Placental Ferroptosis in Gestational Diabetes: A Mechanistic Study
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DOI：10.1155/jdr/2226729.png)
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Abstract
En 中文
Gestational diabetes mellitus (GDM) is a major contributor to adverse pregnancy outcomes. Although the involvement of ferroptosis in GDM pathogenesis has been recognized, the precise mechanisms remain incompletely understood. This study is aimed at investigating the potential regulatory effects of metformin (Met) on ferroptosis in GDM. Patients with GDM were stratified into four groups: diet-controlled (Group 1), nonmedicated (Group 2), Met-treated (Group Met), insulin-treated (Group Ins), alongside healthy controls (Group N). Placental trophoblasts and HTR-8/SVneo cells were subjected to analysis using transmission electron microscopy (ultrastructure), Prussian blue staining (iron detection), CCK-8 assay (proliferation), DCFH-DA probe (reactive oxygen species [ROS]), and biochemical assays (Fe2+, glucose, insulin resistance, and reduced glutathione, GSH). TNF-α and IL-10 levels were measured via flow cytometry. The expression of ATF2, ACSL4, GPX4, and NRF2 was assessed by Western blot and quantitative PCR (qPCR). The ultrastructural characteristics of ferroptosis were observed in both placental trophoblasts and HTR-8/SVneo cells via TEM. Furthermore, Met treatment was found to alleviate placental trophoblast injury more effectively. Both Met and the ferroptosis inhibitor deferoxamine (DFO) enhanced trophoblast proliferation, reduced iron levels and mitochondrial damage, and attenuated oxidative stress and inflammation. Western blotting and PCR analyses indicated that Met and DFO could reverse the expression of ferroptosis-related factors in insulin resistance trophoblasts. Our study confirmed ferroptosis in GDM placental trophoblasts and showed that Met could more effectively mitigate placental trophoblast damage. Met may ameliorate GDM trophoblast injury by regulating ferroptosis via the NRF2/GPX4 pathway, which is linked to reducing oxidative stress and inflammation in GDM trophoblasts.
Keywords:
ferroptosis
gestational diabetes mellitus
metformin
trophoblasts
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