Abstract Early-onset preeclampsia (EOPE), which occurs before 34 weeks of gestation, remains a major cause of maternal and perinatal illness and death worldwide. Traditionally, placental dysfunction in EOPE has been linked to dysregulated apoptosis; however, recent research identifies ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, as an important yet underrecognized mechanism behind trophoblast degeneration. This review critically examines the emerging model of ferroptosis and apoptosis interaction as a feedback loop that drives placental failure in EOPE. Using evidence from single-cell transcriptomics, proteomics, immunohistochemistry, and functional explant assays, we describe the spatial and temporal overlap of lipid reactive oxygen species buildup and caspase-driven apoptosis in EOPE placentas. We focus on key regulatory molecules such as glutathione peroxidase 4, solute carrier family 7 member 1 (SLC7A11), and ferroptosis suppressor protein 1 and clarify their roles in maintaining redox balance, causing mitochondrial failure, and influencing trophoblast survival. Inhibiting ferroptosis in ex vivo models shows promise in reducing subsequent apoptotic pathways, restoring mitochondrial health, and improving blood vessel function. By viewing placental degeneration through the combined lens of ferroptotic and apoptotic processes, this review presents a new understanding of EOPE development. We propose that ferroptosis not only occurs alongside but also actively triggers apoptotic pathways, thereby worsening placental damage and accelerating disease progression. These findings open up new possibilities for treatment and emphasize the importance of carefully designing ethical, pharmacological, and clinical trials to develop ferroptosis-focused therapies for maternal–fetal health in a safe manner.
Andonotopo et al. (Tue,) studied this question.