TGFB1/SMAD3-driven macrophage–myofibroblast transition promotes fibrosis progression in endometriosis

作者：Yuchan Zhong, Xin Huang, Yujing Li, Ruiying Wang, Xinyu Qiao, Fangyuan Li, Lukanxuan Wu, Chang Liu, Yixian Han, Yunwei Ouyang, Dong Liu, Wei Huang · 发表于：Molecular Human Reproduction · 年份：2025 · DOI：10.1093/molehr/gaaf051 · 被引用次数：6 · 研究领域：Endometriosis Research and Treatment、Uterine Myomas and Treatments、TGF-β signaling in diseases

Endometriosis is a chronic gynecological disorder characterized by progressive fibrosis, which is closely associated with clinical symptoms such as dysmenorrhea and infertility. While myofibroblast activation is central to fibrogenesis, the cellular origins and regulatory mechanisms remain incompletely understood. This study demonstrates that the macrophage-myofibroblast transition (MMT) is a novel source of myofibroblasts in endometriosis and is regulated by the TGFB1/SMAD3 signaling pathway. Using single-cell RNA sequencing, we identified a distinct subpopulation of CD68+ macrophages co-expressing ACTA2 and extracellular matrix (ECM)-related genes in the human endometrium, which exhibited a myofibroblast-like transcriptional profile and were predominantly located at a fibrotic terminal state along the pseudotime trajectory. Histological and ultrastructural analyses revealed varying degrees of fibrosis and elevated TGFB1 expression in eutopic and ectopic endometrium in endometriosis patients and mouse models. Immunofluorescence confirmed that MMT-positive cells, co-expressing CD68 and α-SMA, were enriched in endometriotic tissues and primarily derived from M2 macrophages. In mouse models of endometriosis, pharmacological inhibition of TGFB1/SMAD3 signaling significantly reduced the number of MMT-positive cells and attenuated collagen deposition, particularly in the eutopic endometrium. Furthermore, reduced ectopic lesion volume and epithelial ultrastructural damage following...