Curcumin modulates the function of SPP1+ macrophages via NF-κB signaling to alleviate endometriosis.

Endometriosis is a complex gynecological disorder with prominent cellular heterogeneity, and its key pathogenic cell subsets and core molecular mechanisms remain elusive, which restricts the development of effective therapeutic strategies. In this study, we constructed a single-cell atlas of endometriotic lesions via single-cell RNA sequencing, combined with multi-omics analysis, cell-cell communication mining, functional validation and animal experiments. We identified SPP1+ macrophages as the key pathogenic macrophage subset in endometriosis, and uncovered its core mechanism of action: SPP1+ macrophages, as the most significantly enriched core differential cell type in endometriotic lesions, underwent pro-inflammatory reprogramming by activating the NF-κB signaling pathway, thereby regulating the inflammatory microenvironment in lesion sites. Meanwhile, SPP1+ macrophages served as central hubs in the dysregulated signaling network, mediating paracrine crosstalk with stromal and epithelial cells through the SPP1 signaling pathway to drive the pathogenesis of endometriosis. Furthermore, we clarified a novel molecular mechanism underlying curcumin-mediated alleviation of endometriosis: curcumin targeted the NF-κB signaling pathway of SPP1+ macrophages, inhibited NF-κB activation via stable binding to p65, thereby downregulating NFKB1 expression and suppressing SPP1-triggered inflammatory programming, ultimately regulating the inflammatory phenotype of macrophages. Animal experiments suggested that curcumin significantly reduced the volume of ectopic endometriotic lesions and downregulated NFKB1 expression in lesion tissues. This study identified the SPP1+ macrophage/NF-κB signaling axis as a critical driver of endometriosis pathogenesis, and provided novel experimental evidence and molecular mechanistic support for curcumin in the treatment of endometriosis by targeting this axis, laying an important theoretical foundation for the development of targeted therapies for endometriosis.