Ferroptosis, trophoblast lipotoxic damage, and adverse pregnancy outcome.

Programmed cell death is a central process in the control of tissue development, organismal physiology, and disease. Ferroptosis is a recently identified form of programmed cell death that is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. This distinctive form of lipotoxic cell death has been recently implicated in multiple human diseases, spanning ischemia-reperfusion heart injury, brain damage, acute kidney injury, cancer, and asthma. Intriguingly, settings that have been associated with ferroptosis are linked to placental physiology and trophoblast injury. Such circumstances include hypoxia-reperfusion during placental development, physiological uterine contractions or pathological changes in placental bed perfusion, the abundance of trophoblastic iron, evidence for lipotoxicity during the pathophysiology of major placental disorders such as preeclampsia, fetal growth restriction, and preterm birth, and reduced glutathione peroxidation capacity and lipid peroxidation repair during placental injury. We recently interrogated placental ferroptosis in placental dysfunction in human and mouse pregnancy, dissected its relevance to placental injury, and validated the role of glutathione peroxidase-4 in guarding placental trophoblasts against ferroptotic injury. We also uncovered a role for the phospholipase PLA2G6 (PNPLA9) in attenuating trophoblast ferroptosis. Here, we summarize current data on trophoblast ferroptosis, and the role of several proteins and microRNAs as regulators of this process. Our text offers insights into new opportunities for regulating ferroptosis as a means for protecting placental trophoblasts against lipotoxic injury.