Endometriosis (EM) is a chronic inflammatory disease characterized by the growth of endometrial-like tissue outside the uterus, yet its molecular mechanisms remain poorly understood. This study investigated the expression of mucins (MUC1, MUC2, MUC5AC, MUC6, MUC16) and their O-glycans in endometriotic lesions, given their roles in epithelial protection, adhesion, and immune modulation. Using immunohistochemistry, Western blotting, lectin profiling, histochemical staining, and transcriptomic analysis, we compared mucin levels and glycosylation patterns in eutopic and ectopic tissues from women with and without endometriosis and measured mucin-derived tumor markers in serum (CA 125/MUC16 and CA 15-3/MUC1) and peritoneal fluid (CA 125/MUC16). The results showed significant upregulation of all mucins in EM biopsies, with increased MUC1 transcript levels, while MUC6 and MUC16 protein levels did not always align with transcripts. Yet, tumor markers CA 125 and CA 15-3 showed no significant differences between groups. Looking at mucin distribution in biopsies of peritoneal (pEM), deep infiltrating and ovarian EM, MUC1 was significantly overexpressed in lesions of all EM forms, while MUC5AC was significantly elevated in pEM. Lectin analysis revealed specific glycan changes, including elevated core-1 O-glycans and α(1-2)-linked fucosylation, while sialylation remained unchanged. These findings demonstrate consistent mucin dysregulation and glycan alterations, implicating their roles in epithelial adhesion, immune evasion, and lesion persistence. Mucin biology thus emerges as a promising target for diagnostic and therapeutic strategies in endometriosis.

Obesity-associated insulin resistance is driven in part by adipose tissue dysfunction and oxidative stress, yet the role of extracellular mechanisms in modulating insulin signaling remains poorly understood. Here, we show that extracellular Glutathione Peroxidase 3 (GPX3) enhances adipocyte insulin sensitivity and functionalities independent of its canonical peroxidase function. GPX3, a secreted selenoprotein highly expressed in white adipose tissue (WAT), is suppressed in obesity, but whether it actively regulates insulin sensitivity had not been established. We find that WAT GPX3 expression closely mirrors insulin receptor (InsR) expression across a broad range of metabolic parameters in humans and increases dynamically following weight loss. Prolonged therapeutic selenium supplementation in diet-induced obese mice selectively suppressed epididymal WAT oxidative damage, restored GPX3 and InsR expression, and enhanced insulin-stimulated AKT phosphorylation, improving oral glucose tolerance. Mechanistically, recombinant GPX3 extracellularly administered at physiological concentrations induced InsR expression across multiple adipocyte models, including pre-adipocytes, epididymal WAT explants, and adipocyte organoids, by promoting binding of the transcription factor Specificity Protein 1 (SP1) to the Insr promoter, while knockdown of GPX3 completely blocks SVF adipogenesis. These effects rely on the structural integrity, rather than selenocysteine-dependent activity. Thus, we identify a GPX3-SP1-InsR signaling axis in adipose tissue insulin sensitivity, suggesting GPX3 is a novel paracrine mediator of metabolic health and a potential therapeutic target to reinstate WAT insulin sensitivity in obesity and type 2 diabetes. Graphical