Estrogen-induced NETs promote aseptic inflammation via NKCC1 [human]

Although the formation of neutrophil extracellular traps (NETs) is caused by inflammation-related factors, it remains unclear whether endogenous hormones promote NET formation. Here, we investigate NET formation between infection-driven inflammatory endometrium and estrogen-induced hyperplastic endometrium by single-cell multiomics analysis. We identified a unique neutrophil subpopulation (CD24high neutrophil) involved in estrogen-driven NET formation. Estrogen-induced NETs mainly form due to the imbalance of histone caused by estrogen receptors. Inhibition of NETs significantly ameliorated endometrial hyperplasia (EH) in a murine model. Mechanistically, NETs promote cell proliferation by binding to NKCC1 on epithelial cells. Aspirin was screened to inhibit NET formation and alleviated EH in cynomolgus monkey. This study provides a novel nonhormone replacement therapy to treat patients with estrogen abnormalities by targeting NETs. scRNA-seq of normal endometrium (7); scRNA-seq of endometrial hyperplasia (10); scRNA-seq of endometritis (7); scATAC-seq of normal endometrium (4); scATAC-seq of endometrial hyperplasia (2); scATAC-seq of endometritis (2); ST-seq of normal endometrium (1); ST-seq of endometrial hyperplasia (1). **The submitter declares that raw data were not submitted due to patient privacy concerns**