The endothelin-1/TLR4/NF-κB/NLRP3 inflammasome axis in preeclampsia: a review of a pathological feed-forward loop and therapeutic frontier.

Preeclampsia remains a primary cause of maternal and neonatal mortality, yet no definitive therapy targets the placenta itself, and current management is largely limited to delivery. Recent research has identified a self-sustaining, feed-forward molecular loop involving exaggerated placental endothelin-1 (ET-1) signaling, amplified by the TLR4/NF-κB/NLRP3 inflammasome axis, as a central driver of the disease. This axis translates placental hypoxia and oxidative stress into sustained maternal endothelial injury; while ET-1 acts as a potent vasoconstrictor that stimulates the NLRP3 inflammasome, the resulting inflammasome-driven IL-1β further upregulates ET-1 production. This inflammatory engine promotes the release of anti-angiogenic factors such as sFlt-1 and soluble endoglin. Evidence from human primary trophoblast cultures, placental explants, and animal models demonstrates that interrupting this axis can collapse the pathological cycle. Selective ET1_A receptor antagonists and direct NLRP3 inhibitors have shown high efficacy in reducing anti-angiogenic output and restoring maternal vascular function, while repurposed drugs like sulfasalazine and pravastatin offer immediate translational opportunities. Ultimately, the ET-1/NLRP3 axis represents a highly actionable target for modifying the course of preeclampsia in a significant subset of patients, particularly those with hypoxic, metabolic, or TLR4-driven inflammatory phenotypes. Genetically stratified trials are now needed to identify who benefits most. However, the relative contribution of this axis varies across the clinical and genetic heterogeneity of preeclampsia, necessitating biomarker-guided trial design.