UBE2S-mediated deubiquitination of GLUT1 via USP10 regulates glucose metabolic reprogramming and immune microenvironment to promote fibrosis in endometriosis

作者：Baoju Wang, Hu Li, Zhen Zhang, Yue Yin, Linyao Zheng, Han Wu, Yan Cheng, Guangmei Zhang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07436-9 · 被引用次数：4 · 研究领域：Endometriosis Research and Treatment、Uterine Myomas and Treatments、Reproductive System and Pregnancy

BACKGROUND: Endometriosis (EM) is a chronic inflammatory disorder characterized by the growth of ectopic endometrial-like tissue and fibrosis. Metabolic reprogramming, particularly enhanced glycolysis, and immune microenvironment dysregulation are key features of EM progression. However, the underlying molecular mechanisms remain poorly understood. METHODS: This study integrated transcriptomic analysis, immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, and ubiquitination assays to systematically investigate the role of Ubiquitin-Conjugating Enzyme E2S (UBE2S) in regulating glucose metabolism and immune modulation in EM. In vitro, cell experiments, and mouse models were used to validate its effects on glycolysis, macrophage polarization, and fibrosis. RESULTS: UBE2S was significantly upregulated in ectopic endometrial stromal cells. IP-MS analysis identified glucose transporter 1 (GLUT1) and Ubiquitin-Specific Peptidase 10 (USP10) as key interacting proteins of UBE2S. Mechanistic studies revealed that UBE2S mediates K48-linked deubiquitination of GLUT1 through USP10, stabilizing GLUT1 protein and enhancing glycolytic activity. This metabolic reprogramming leads to lactate accumulation, which induces M2 macrophage polarization and secretion of transforming growth factor β1 (TGF-β1), thereby promoting fibroblast-to-myofibroblast transition and accelerating fibrosis in the lesions. The UBE2S inhibitor cephalomannine significantly downregulated GLUT1 expressio...