Eutopic macrophages facilitate endometriosis progression via ferroptosis-mediated release of S100A9.

Abstract

Endometriosis is a chronic inflammatory disorder in which immune cells, specifically macrophages, play a pivotal yet incompletely understood role. Aberrations within the eutopic endometrium are implicated in the initiation and progression of endometriosis. In this study, we reported a notable increase in the proportion of a distinct S100A9+ macrophage subpopulation undergoing ferroptosis in the eutopic endometrium of endometriosis patients compared with normal endometrium, as evidenced by single-cell RNA sequencing and experimental validation. Furthermore, we confirmed that Ammonium iron (III) citrate-treated macrophages upregulate S100A9 through the NF-κB pathway in vitro. Subsequent cell function experiments and endometriosis mouse models revealed that S100A9 promotes the development of endometriosis by facilitating angiogenesis. Notably, the S100A9 inhibitor Tasquinimod effectively reduced angiogenesis and thereby reduced ectopic lesions in mice. These results indicated that S100A9+ macrophages represent a potential therapeutic target for endometriosis.