Targeting the Wnt signaling network in endometriosis: mechanistic insights and translational opportunities†

Endometriosis is a chronic gynecological disorder defined by the growth of endometrial-like tissue outside the uterus, driven by estrogen-dependent inflammation and progressive fibrosis. According to available data, remodeling and persistent abnormal activation of the Wnt/β-catenin signaling network constitute one of the main molecular bases underlying its progression. Pathological characteristics of this disease include increased proliferation and anti-apoptotic potential of ectopic endometrial cells, as well as invasive phenotypes and progressive fibrosis. The Wnt/β-catenin pathway contributes to these changes through multiple levels of regulation. The pathway modifies the ligand-receptor spectrum within ectopic lesions at the level of ligand-receptor interactions. Certain canonical or non-canonical branches are more likely to be activated due to imbalanced expression of Wnt ligands and Frizzled receptors. This biased activation promotes β-catenin accumulation and nuclear translocation. In parallel, the pathway is modulated by Wnt antagonists and microRNAs. Additionally, it interacts with estrogen-progesterone imbalance, inflammatory mediators, and the immune microenvironment. The pathological processes of endometriosis are co-shaped by these signals. This review provides an organized overview of the roles of Wnt signaling in endometriosis. First, the upstream regulators of Wnt signaling and its interactions with the microenvironment are summarized. Second, the pathological effects of prolonged activation are explained, emphasizing epithelial-mesenchymal transition, fibrosis, and immune evasion. Third, the therapeutic potential of targeting this pathway is assessed, including small-molecule inhibitors, drug repurposing approaches, and nucleic acid- or epigenetic-based techniques. Finally, we propose a conceptual framework for precision treatment and targeted intervention in endometriosis, aiming to offer clinically relevant reference points.