The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis.

Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.