Pyroptosis in Preeclampsia: Placenta‐to‐Maternal Organ Communication, Molecular Mechanisms, and Therapeutic Targets

ABSTRACT Preeclampsia (PE) is a life‐threatening pregnancy‐specific complication with complex pathogenesis, mainly involving poor placentation and endothelial dysfunction. Pyroptosis, an inflammatory regulated cell death mediated by gasdermin proteins and inflammatory caspases, has emerged as a key participant in PE pathogenesis. Excessive pyroptosis in trophoblasts impairs invasion and spiral artery remodeling, leading to placental ischemia/hypoxia, whereas aberrant pyroptosis in endothelial cells (ECs) exacerbates inflammatory responses and vascular dysfunction, with both processes contributing to PE progression. Notably, pyroptosis activation at the maternal‐fetal interface initiates a placenta‐to‐maternal interorgan communication axis, whereby pyroptosis‐associated mediators—including IL‐1β, IL‐18, HMGB1, and cellular debris are released into the maternal circulation, remotely perturbing vascular endothelial function and damaging distant maternal organs to trigger the systemic multiorgan manifestations of PE. This review summarizes the molecular mechanisms (canonical, non‐canonical, and other pathways) and key regulatory factors (reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, autophagy, and non‐coding RNAs) of pyroptosis, and focuses on its roles in trophoblast cells and ECs during PE development. Critically, we systematically categorize and highlight potential therapeutic agents targeting distinct nodes of the pyroptosis pathway, including direct inhibitors of the NLRP3 inflammasome, caspase‐1, gasdermin D, and the IL‐1β/IL‐1R axis, as well as their upstream regulators. In conclusion, this review identifies remaining research gaps and emphasizes that targeting pyroptosis, particularly the pyroptosis‐mediated interorgan communication axis, provides a promising novel strategy for the diagnosis and treatment of PE.