p53-mediated suppression of the SLC7 A11/GPX4 signaling pathway promotes trophoblast ferroptosis in preeclampsia.

Background: Ferroptosis is an iron-dependent form of non-apoptotic cell death that occurs through increased plasma membrane phospholipid peroxidation in the context of impaired plasma membrane phospholipid peroxide repair systems. It has been reported that p53 can inhibit the expression of cysteine/glutamate reverse transporter solute carrier family 7, member 11 (SLC7A11), a key component of system Xc-, thus inhibiting cysteine uptake and promoting reactive oxygen species (ROS) accumulation as an important part of cell ferroptosis. Preeclampsia (PE) is an idiopathic hypertensive disease of pregnancy. Spiral artery insufficiency and impaired placental development are present at all stages, leading to placental hypoperfusion, ischemia, and hypoxia. However, the role of ferroptosis, particularly p53-mediated trophoblast ferroptosis, in placental dysfunction during PE remains unclear.

Results: In PE placental tissues, malondialdehyde (MDA) and total iron levels were elevated, and trophoblasts exhibited typical ferroptosis-associated morphological changes. Additionally, p53 mRNA and protein expression and the percentage of p53-positive cells were increased, while SLC7A11 and GPX4 mRNA and protein expression and the percentage of positive cells were decreased. VEGFR1 protein expression was upregulated, whereas VEGFA and PLGF protein expression was downregulated. p53 protein expression was negatively correlated with the expression of proteins in the SLC7A11/GPX4 signaling pathway, VEGFA, and PLGF. Conversely, there was a positive correlation between p53 expression and MDA, total iron concentration, and VEGFR1. In vitro, the ferroptosis inducer erastin increased ROS levels in trophoblast cells. The ferroptosis inhibitor Fer-1, the apoptosis inhibitor Z-VAD-FMK, and the necrosis inhibitor Nec-1 failed to prevent erastin-induced ROS elevation. In p53 + / + trophoblasts, erastin-induced ROS elevation was more pronounced than that in p53 - / - and control cells, and angiogenesis was impaired. In pregnant rats, p53 + / + placentas exhibited increased MDA and total iron levels, ferroptosis-like morphological changes in trophoblasts, and reduced CD34 expression. p53 protein expression was negatively correlated with CD34 expression.

Conclusion: This study confirmed that trophoblast ferroptosis occurs in the pathological state of PE and that trophoblast are specifically sensitive to ferroptosis. p53 can mediate the SLC7A11/GPX4 signaling pathway to promote ferroptosis of trophoblast cells in the pathogenesis of PE. It is also speculated that increased p53 reactivity may mediate impaired angiogenesis in placental tissues.