The von Hippel-Lindau (VHL) protein (pVHL) functions as a potent tumor suppressor by mediating the degradation or inactivation of various substrates, including HIFα and Akt. However, pVHL is frequently downregulated in numerous cancers harboring wild-type VHL , and underlying mechanisms remains elusive. Aberrant glucose metabolism is a hallmark of cancer, driving tumor progression and therapeutic resistance. Despite this, the connection between glucose homoeostasis and pVHL turnover and functions has yet to be defined. In this study, we demonstrate that dysregulated glucose metabolism destabilizes pVHL in pancreatic ductal adenocarcinoma (PDAC), colorectal, and ovarian cancer cells. Mechanistically, energy stress induced by glucose starvation, 2-deoxyglucose (2-DG), or metformin activates AMP-activated protein kinase (AMPK), which subsequently phosphorylates and activates BAP1, a deubiquitinase whose specific function in targeting pVHL for deubiquitination and stabilization had not been previously characterized. Specifically, AMPKα phosphorylates BAP1 at residues S123, S469, and S583, enhancing the interaction between BAP1 and pVHL and promoting pVHL stabilization and tumor-suppressive function both in vitro and in vivo. Conversely, disrupting BAP1 phosphorylation through AMPKα depletion or reconstitution with a phosphorylation-defective BAP1 mutant (S123A/S469A/S583A) abolishes the BAP1-pVHL interaction, leading to impaired pVHL stabilization and accelerated tumor progression in cancer cell lines and patient-derived xenograft models. Clinically, our analysis reveals a positive correlation between levels of phosphorylated AMPKα (p-AMPKα), phosphorylated Ser123-BAP1 (pSer123-BAP1), and pVHL levels in PDAC, colorectal cancer, and ovarian cancer specimens. Collectively, these findings elucidate a novel mechanism linking dysregulated glucose metabolism to compromised function of the BAP1-pVHL tumor-suppressive axis. Our results suggest that therapeutic strategies designed to activate this pathway may represent a promising approach for treating cancers characterized by downregulated wild-type VHL and aberrant glucose metabolism.

Background: Ankylosing spondylitis (AS), a chronic inflammatory disorder affecting axial joints, is frequently complicated by uveitis. However, the molecular mechanisms linking AS to secondary uveitis remain poorly understood. Methods: We integrated transcriptomic datasets from AS (GSE73754) and uveitis (GSE194060) cohorts to identify shared molecular pathways. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning (LASSO, SVM-RFE, random forest) were combined to prioritize biomarkers. Molecular docking was performed to evaluate drug-target interactions using Vina scores (≤−7 kcal/mol threshold). Results: Cross-disease analysis revealed 697 overlapping dysregulated genes (481 upregulated, 216 downregulated), enriched in GTPase signaling and immune pathways. WGCNA identified disease-specific co-expression modules (AS: brown/tan modules, r = 0.39/0.35; uveitis: brown module, r = 0.49). Machine learning nominated HLX and SLC25A20 as core biomarkers, demonstrating robust diagnostic accuracy in discovery (AS AUC: 0.688/0.700; uveitis AUC: 0.867/0.838) and validation cohorts (AS AUC: 0.653/0.667; uveitis AUC: 0.662/0.736). Immune profiling linked HLX to neutrophil infiltration (r = 0.55, p < 0.01) and SLC25A20 to T helper cell regulation (r = 0.36, p < 0.01). Molecular docking identified high-affinity ligands for SLC25A20, including amiodarone (−8.0 kcal/mol) and estradiol (−7.7 kcal/mol), with folic acid showing dual binding potential (HLX: −7.5 kcal/mol; SLC25A20: −8.2 kcal/mol). Conclusion: HLX and SLC25A20 emerge as immunologic regulators bridging AS and uveitis pathogenesis. These findings provide actionable targets for precision diagnostics and therapeutic development in AS-associated uveitis.