Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation

Endometriosis (EM) is driven by immune dysregulation and macrophage dysfunction, yet the underlying mechanisms remain unclear. Here, metabolomic profiling revealed excessive itaconate accumulation in EM lesions, primarily due to elevated cis-aconitate decarboxylase 1 (ACOD1) expression in ectopic stromal cells (ESCs). ESC-derived itaconate was internalized by peritoneal macrophages, where it suppressed pro-inflammatory activity and phagocytosis, thereby facilitating ESC survival and dissemination. Mechanistically, itaconate exerted dual regulatory effects on macrophages: it activated NRF2 signaling to repress the transcription of pro-inflammatory genes, and it enhanced lysosomal acidification, thereby reducing lysosomal calcium release, which in turn inhibited p38–MAPK activation and further attenuated pro-inflammatory gene expression. In vivo, ACOD1 inhibition restored macrophage function and reduced lesion burden, while exogenous 4-octyl itaconate aggravated disease progression. These findings define a novel “ESC–ACOD1–itaconate–macrophage” axis that mediates immunosuppression in EM and identify ACOD1 as potential therapeutic targets. ESC-derived itaconate remodels macrophage function and drives immune microenvironment dysregulation in endometriosisEctopic endometrial stromal cells (ESCs) in endometriosis upregulate ACOD1, leading to increased itaconate synthesis and secretion. This ESC-derived itaconate is taken up by peritoneal macrophages, where it elevates lysosomal acidity, inhibits NOX2 and MCOLN2-mediated calcium signaling, and activates NRF2-driven antioxidant responses. These coordinated changes suppress macrophage pro-inflammatory and clearance functions, resulting in immune microenvironment dysregulation and facilitating lesion persistence. Our findings uncover a novel ESC–ACOD1–itaconate–macrophage metabolic–immune axis, providing new insight into endometriosis pathogenesis and suggesting promising targets for precision therapy.