Protective effect of annexin A5 against preeclampsia-like phenotypes in mice through the NF-κB/NLRP3 inflammasome pathway

BACKGROUND AND OBJECTIVES: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality, yet effective targeted therapies remain limited. This study aimed to investigate the therapeutic potential of annexin A5 (ANX A5) in PE and to elucidate the underlying mechanisms based on metabolomic profiling. METHODS: A PE-like mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS, 20 μg/kg/day) from gestational day (GD) 7.5 to 17.5, followed by intravenous administration of ANX A5 (50 μg/kg/day) in the treatment group. In vitro, LPS-stimulated HTR-8/Svneo trophoblast cells were treated with either ANX A5 or NLRP3 inhibitor. Placental metabolite profiling was performed using liquid chromatography-tandem mass spectrometry. Placental morphology and NF-κB/NLRP3 inflammasome markers were evaluated by western blotting and enzyme-linked immunosorbent assay. RESULTS: ANX A5 administration markedly attenuated high blood pressure, proteinuria, and adverse pregnancy outcomes in PE-like mice. Metabolic alterations associated with ANX A5 were predominantly enriched in the NF-κB/NLRP3 inflammasome pathway. Correspondingly, ANX A5 treatment downregulated the elevated placental expression of NLRP3, caspase-1, and interleukin-1β in PE-like mice. Furthermore, in HTR-8/Svneo cells, ANX A5 effectively suppressed the inflammatory responses by inhibiting the NF-κB/NLRP3 inflammasome signaling pathway, thereby restoring trophoblast migratory capacity. CONCLUSION: These findings demonstrate that ANX A5 confers significant protection in a PE mouse model, which is mediated through inhibition of the NF-κB/NLRP3 inflammasome pathway and modulation of placental metabolism. This study highlights the potential of ANX A5 as a novel therapeutic strategy for PE.