Cadmium exposure activates ferroptosis through downregulated PPARγ expression in preeclampsia placenta

This study aimed to investigate mechanism of cadmium activated ferroptosis in preeclampsia placenta. Placenta were collected to detect expressions of PPARγ and ferroptosis markers. JEG3 cells were treated with CdCl₂ (20 μM) and PPARγ siRNA for 24 h to investigate whether cadmium exposure activated ferroptosis and role of PPARγ in ferroptosis. JEG3 cells were treated with RSL3 (0.5 μM), CdCl₂, PPARγ siRNA and ferrostatin-1 (1 μM) to demonstrate association between ferroptosis and preeclampsia. Ferroptosis was activated in preeclampsia, with increased peroxiredoxin-3 and decreased GPX4 expressions, increased MDA concentration, enhanced 4HNE signal and Fe^2 + accumulation. Protein expression and nuclear translocation of PPARγ were significantly down-regulated in preeclampsia placenta. Ferroptosis was activated, protein expression and nuclear translocation of PPARγ were significantly decreased in CdCl₂-treated cells. PPARγ siRNA transfection led to ferroptosis activation. Placental growth factor (PLGF) expression was significantly down-regulated in preeclampsia placenta, CdCl₂-treated, RSL3-treated and PPARγ siRNA-transfected cells. Glutathione concentration was decreased in preeclampsia placenta and CdCl₂-treated cells. CdCl₂ pretreatment exacerbated PPARγ siRNA transfection-induced increase in HO1 expression and decrease in PLGF expression. Rosiglitazone (1 μM) protected against CdCl₂ induced ferroptosis, ferrostatin-1 restored PLGF expression in CdCl₂ and PPARγ siRNA induced ferroptosis in cells. Our results indicate that cadmium exposure activates ferroptosis through downregulated PPARγ in preeclampsia placenta.