Endometriosis (EM) represents a persistent inflammatory condition marked by the presence of endometrium-like tissue outside its normal location and associated fibrotic changes. Alterations in metabolism, notably heightened glycolytic processes, along with disruptions in the immune milieu, constitute prominent aspects of EM advancement. Nonetheless, the precise molecular pathways involved are still inadequately clarified. The present investigation employed a combination of transcriptome profiling, immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, and ubiquitination experiments to thoroughly explore the function of Ubiquitin-Conjugating Enzyme E2S (UBE2S) in controlling glucose metabolism and immune regulation within EM. Cellular assays in vitro, along with murine models, were utilized to confirm its influence on glycolytic pathways, macrophage polarization states, and fibrotic development. Expression of UBE2S was markedly elevated in stromal cells from ectopic endometriotic sites. Through IP-MS, GLUT1 and USP10 emerged as principal partners interacting with UBE2S. Detailed mechanistic examinations demonstrated that UBE2S facilitates K48-linked deubiquitination of GLUT1 via USP10, thereby maintaining GLUT1 protein stability and augmenting glycolytic flux. Such metabolic shifts result in increased lactate buildup, which in turn triggers M2-type macrophage polarization and release of TGF-β1, consequently driving the conversion of fibroblasts to myofibroblasts and hastening lesion fibrosis. Administration of the UBE2S inhibitor cephalomannine notably reduced GLUT1 levels, curtailed glycolysis, impeded M2 polarization, and mitigated fibrosis in ectopic sites. The research elucidates the pathway whereby the UBE2S–USP10–GLUT1 axis modulates the immune surroundings and advances fibrosis in EM via alterations in metabolism. These observations yield fresh perspectives on EM pathophysiology and establish a rationale for pursuing UBE2S as a target in treatment approaches.
