UDP‐Glucose‐6‐Dehydrogenase Mediated O‐GlcNAcylation of Tight Junction Protein 1 Suppresses Metastasis in Renal Cell Carcinoma

Tumor metastasis remains the leading cause of postoperative recurrence and mortality in patients with clear cell renal cell carcinoma (ccRCC). Although aberrant glucuronic acid metabolism and O-GlcNAcylation are closely associated with tumor progression, the mechanism by which these pathways intersect to regulate ccRCC metastasis remains poorly understood. Here, an orthotopic ccRCC mouse model coupled with comparative proteomic analysis of primary and metastatic lesions identified UDP-glucose-6-dehydrogenase (UGDH) as a pivotal suppressor of metastasis in ccRCC. In vitro and in vivo functional assays confirmed that UGDH overexpression markedly suppressed the invasion and migration of ccRCC cells. Mechanistically, we demonstrated that the E3 ubiquitin ligase TRIM25 facilitates UGDH degradation via K48-linked polyubiquitination, whereas UGDH modulates the expression of tight junction protein 1 (TJP1) via O-GlcNAcylation. Notably, pharmacological inhibition of O-GlcNAcylation with OSMI-1 effectively impeded metastasis in both cellular and animal models. This study reveals a novel tumor-suppressive role for UGDH and highlights the potential of the TRIM25-UGDH-TJP1 axis for diagnostic and therapeutic strategies in metastatic ccRCC.