Hypoxia-induced regulations of cell adhesion molecules and their implications for pathogenesis, diagnosis, and treatment of endometriosis.

Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, affecting up to 10% of women of reproductive age. Despite extensive research, its pathogenesis remains incompletely understood, and clinically useful non-invasive diagnostic tools are still lacking. Increasing evidence identifies hypoxia as a key microenvironmental factor promoting lesion establishment and persistence. Cellular responses to hypoxia are mediated by hypoxia-inducible factor 1 alpha (HIF-1α), which coordinates transcriptional programs involved in angiogenesis, inflammation, estrogen biosynthesis, extracellular matrix remodeling, and cell survival. A critical consequence of this hypoxia-driven signaling is the dysregulation of cell adhesion molecules (CAMs), which directly facilitates ectopic implantation and lesion progression. Adhesion-related molecules implicated in endometriosis include integrins, selectins, cadherins (E-cadherin, N-cadherin, CDH12, T-cadherin), claudins, intercellular adhesion molecules (ICAMs), matrix metalloproteinases (MMPs), and anthrax toxin receptor 2 (ANTXR2). Altered expression and activity of these molecules enhance attachment to the peritoneum, immune cell recruitment, angiogenesis, and extracellular matrix remodeling, thereby sustaining chronic inflammation and lesion growth. Beyond their pathogenetic role, CAMs are increasingly recognized as clinically relevant diagnostic and therapeutic targets in endometriosis. Within this group, P-selectin emerges as a particularly promising candidate, as its association with disease-related inflammatory activity supports its potential utility as a non-invasive biomarker and as a therapeutic target, exemplified by preclinical studies using the monoclonal antibody inclacumab. In parallel, growing evidence supports the diagnostic relevance of other adhesion-related molecules, including N-cadherin, ICAM-1, and MMP-9. Furthermore, therapeutic strategies targeting adhesion-related pathways - either directly or through modulation of hypoxia-responsive signaling - have demonstrated promising results in preclinical studies. This review highlights cell adhesion molecules as central effectors of hypoxia-driven mechanisms in endometriosis and underscores their relevance for the development of mechanism-based diagnostic and therapeutic approaches, complementing existing hormonal and symptomatic treatments.