IL-8-driven neutrophil NETosis triggers endothelial apoptosis and exacerbates preeclampsia.

BACKGROUND: Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide, characterized by hypertension, proteinuria, and placental dysfunction. Increasing evidence implicates aberrant immune activation and vascular injury in PE pathogenesis, but the upstream signals and cellular mechanisms remain incompletely understood. METHODS: We integrated transcriptomic profiling, maternal serum cytokine analysis, and placental immunohistochemistry to identify dysregulated chemokines. Human and murine trophoblasts were stimulated under hypoxia or LPS challenge to assess IL-8/CXCL1 production. Functional assays of NET formation and endothelial apoptosis were conducted in trophoblast–neutrophil–endothelium co-culture systems. Finally, we tested the therapeutic effects of neutralizing anti-CXCL1 antibody or the CXCR1/2 inhibitor SX682 in LPS-induced murine models of PE. RESULTS: We found that IL-8 was markedly elevated in PE patients and correlated with disease severity. Hypoxia- or LPS-stimulated trophoblasts secreted abundant IL-8/CXCL1, which recruited and activated neutrophils to undergo NETosis. NETs directly induced endothelial mitochondrial dysfunction and apoptosis, resulting in vascular injury. Pharmacological blockade of IL-8 signaling, either by CXCL1 neutralization or CXCR1/2 inhibition, significantly ameliorated hypertension, proteinuria, and fetal growth restriction in murine PE models, without altering placental weight or gross morphology. CONCLUSION: Our findings define a trophoblast–neutrophil–endothelium axis in which IL-8–driven NETosis exacerbates vascular pathology in PE. Targeting IL-8/CXCL1-CXCR1/2 signaling interrupts this pathogenic circuit, restores endothelial function, and improves maternal and fetal outcomes. These results highlight IL-8 signaling as a promising therapeutic target for PE. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08084-3.