Objective: To investigate the mechanism by which DEX regulates ferroptosis through GRa and autophagy to affect the function of placental trophoblast cells. Design: Exploration at clinical and cellular levels. Setting: Dex-treated and untreated groups were set. Population or Sample: Placenta tissue and cells (HTR-8/SVneo cells and TEV-1 cells). Methods: Prussian blue staining, IHC detection, Fe2+ level detection, electron microscope detection, CCK-8 detection, lipid oxidation level detection, Calcein-AM/PI staining detection level detection, ROS level test, MDA level detection, GSH level detection, GPX4 activity detection, WB detection and autophagy flow detection. Main Outcome Measures: The level of ferroptosis, the level and activity of AMPKα/BECN1 and ATG5/ATG7/NCOA4 signaling pathways, and the level of autophagy in placental trophoblast cells were evaluated Results: First, we found that DEX significantly increased the level of ferroptosis in placental tissue in women at risk of preterm birth. Next, we evaluated the effects of DEX and Ferrostatin 1 or DFOM treatment, the ferroptosis inhibitors, on placental trophoblast cell viability and ferroptosis levels. DEX decreased cell viability and increased iron accumulation and lipid peroxidation; Ferrostatin-1 or DFOM treatments could reverse these effects. Mechanically, DEX regulated autophagy and the protein levels of AMPKα/BECN1 and ATG5/ATG7/NCOA4 signaling pathways by inhibiting its receptor GRα. In addition, AMPKα inhibitors Comp C, siAMPKα, siBECN1, siATG5, siATG7 and siNCOA4 could reverse the inhibitory effect of DEX on the survival of placental trophoblast cells. In addition, AMPKα/BECN1 axis triggered autophagy activation and ATG5/ATG7/ NCOA4-mediated autophagy ferritin degradation were found to be associated with DEX induced ferroptosis in placental trophoblast cells. As demonstrated by the inhibition of autophagy by Comp C, siAMPKα and siBECN1, knockdown of ATG5, ATG7 and NCOA4 reduced intracellular iron accumulation and lipid peroxidation, and increased the protein expression of ferritin (FTH1), thus reducing the influence of the ferroptosis inducer erastin. Conclusions: This study provided experimental support for the adverse effects of DEX on preterm pregnancy-related disorders, and found that AMPKα/BECN1 and ATG5/ATG7/NCOA4 were key pathways by which DEX induced autophagy dependent ferroptosis in placental trophoblastocytes.