Regulated Cell Death at the Maternal-Fetal Interface in Preeclampsia: Apoptosis, Necroptosis, Pyroptosis, Ferroptosis, Autophagic Cell Death, and Cuproptosis - A Narrative Review.

Preeclampsia is a pregnancy-specific multisystem disorder in which placental stress is translated into maternal endothelial dysfunction, hypertension, and end-organ injury. This narrative review summarizes how six regulated cell death modalities-apoptosis, necroptosis, pyroptosis, ferroptosis, autophagic cell death, and cuproptosis-participate in this process at the maternal-fetal interface. Hypoxia, oxidative stress, endoplasmic reticulum stress, metabolic disturbance, and altered metal homeostasis converge on trophoblasts, decidual immune cells, and placental endothelial cells. Apoptosis reduces trophoblast mass and increases apoptotic debris; necroptosis releases DAMPs via the RIPK1/RIPK3/MLKL axis; pyroptosis activates inflammasome-caspase-gasdermin signaling and releases IL-1β and IL-18; ferroptosis generates iron-dependent lipid peroxidation products; autophagy and mitophagy determine whether stressed cells recover or progress to death; and cuproptosis links copper overload to mitochondrial proteotoxic stress. These death-related products, including syncytiotrophoblast debris, extracellular vesicles, cytokines, oxidized lipids, and mitochondrial danger signals, may disseminate from the placenta into maternal organs and amplify systemic vascular inflammation. By comparing the triggers, execution mechanisms, products, and clinical implications of each cell death modality, this review proposes an integrative model in which a self-amplifying placental cell death network drives the clinical syndrome of preeclampsia. We also discuss candidate biomarkers and therapeutic strategies, while emphasizing that future studies should define temporal dynamics, disease subtype specificity, and maternal-fetal safety before clinical translation.