O-GlcNAc modification regulates autophagy and apoptosis in endometriosis

Endometriosis is a common, chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterine cavity, frequently associated with significant morbidities such as pelvic pain and infertility. Elucidating its underlying pathogenic mechanisms is therefore of critical importance. O-GlcNAcylation, a ubiquitous post-translational modification, plays pivotal roles in diverse biological processes, yet its involvement in endometriosis progression remains largely unexplored. Here, we demonstrate that aberrantly elevated O-GlcNAcylation contributes to endometriosis pathogenesis by modulating autophagy and apoptosis. Specifically, O-GlcNAcylation levels were elevated in both ectopic and eutopic endometrial tissues, coinciding with compromised autophagic function. In 12Z endometriotic cells, the targeted downregulation of O-GlcNAcylation inhibited cell proliferation while promoting autophagy and apoptosis, whereas its upregulation yielded opposite effects. Furthermore, concurrent inhibition of autophagy reversed the pro-apoptotic effects induced by reduced O-GlcNAcylation. Mechanistically, attenuating O-GlcNAcylation promoted autophagy and apoptosis via the inhibition of the mTOR signaling pathway, an effect potentially mediated by decreased O-GlcNAcylation of Raptor, a core mTORC1 component. In vivo studies further corroborated that suppressing O-GlcNAcylation inhibits ectopic lesion growth and enhances both autophagy and apoptosis. Collectively, our findings reveal that O-GlcNAcylation drives endometriosis progression by regulating autophagy and apoptosis via the mTOR pathway, providing novel mechanistic insights and highlighting potential therapeutic targets for precision interventions.