Regulatory role of ATF2 in trophoblast ferroptosis via the PI3K/Akt/Nrf2 pathway in gestational diabetes mellitus.

AIMS/INTRODUCTION: To investigate the expression of ATF2 in GDM patients and its impact on trophoblast viability and ferroptosis, as well as to explore the mechanism by which ATF2 regulates ferroptosis and affects trophoblast function in GDM. MATERIALS AND METHODS: Placental tissues from pregnant women with normal glucose levels and those with GDM were collected. The expression of ATF2 was detected using immunohistochemistry and western blot analysis, and its correlation with clinical maternal and neonatal outcomes was analyzed. The trophoblast cell line HTR8/SVneo was infected with ATF2-overexpressing or interfering lentivirus and stimulated with high glucose to assess changes in cell viability and ferroptosis. Transcriptome sequencing and functional experiments were conducted to identify potential downstream pathways of ATF2. RESULTS: We found that ATF2 is highly expressed in GDM placental tissues and in trophoblast cells under high glucose conditions, and its overexpression is significantly positively correlated with increased levels of ferritin (P = 0.010), triglycerides (P = 0.039), and total cholesterol (P = 0.044) in GDM patients. Exogenous ATF2 expression further suppresses the proliferation of HTR8/SVneo cells under high glucose stimulation and promotes an increase in ferroptosis. Mechanistically, ATF2 targets the inhibition of the PI3K/Akt/Nrf2 pathway, reducing Nrf2 nuclear translocation and decreasing glutathione peroxidase 4 (GPX4) expression, thereby promoting ferroptosis in trophoblast cells and reducing their viability. CONCLUSIONS: ATF2 regulates ferroptosis and impacts trophoblast function in GDM through the PI3K/Akt/Nrf2 pathway, serving as a significant biomarker and a potential target for prevention and treatment of GDM.