Abstract
Background: Increasing evidence implicates the NF-κB/p65 signaling pathway in the progression of prostate cancer (PC) and the development of resistance to androgen deprivation therapy. This study aimed to investigate the potential role of UHRF1, a key epigenetic regulator, in modulating NF-κB activity, and to evaluate its association with clinicopathological features and clinical outcomes in PC patients. Methods: Differentially expressed genes (DEGs) were identified using the GSE104749 dataset. UHRF1 expression was validated across TCGA and GEO cohorts and further confirmed in clinical specimens using Western blotting and immunohistochemistry. Survival outcomes were evaluated using Kaplan-Meier and Cox regression analyses. A prognostic model was built incorporating UHRF1, Gleason score, and PSA, with validation via ROC curves and nomogram. Functional studies assessed the impact of UHRF1 silencing or overexpression on cell proliferation, apoptosis, cell cycle, glucose metabolism, and NF-κB signaling. Co-immunoprecipitation was used to assess the physical interaction between UHRF1 and p65. Results: Higher Gleason scores, advanced clinical stage, lymph node involvement, and distant metastases were all positively connected with UHRF1 expression, which was markedly overexpressed in PC tissues. High UHRF1 expression was associated with shorter overall survival (OS) and disease-free survival (DFS), and independently predicted biochemical recurrence (BCR). A prognostic model incorporating UHRF1 achieved a high predictive accuracy (C-index = 0.752), and the corresponding nomogram demonstrated strong reliability in individualized risk assessment. In vitro, UHRF1 promoted tumor progression by enhancing proliferation, inhibiting apoptosis, driving aerobic glycolysis, and regulating the cell cycle. Mechanistically, UHRF1 bound to p65, promoted its phosphorylation, and activated NF-κB signaling. Conclusion: UHRF1 contributes to prostate cancer progression by driving tumor growth, metabolic reprogramming, and NF-κB activation. It holds promise as both a prognostic biomarker and a potential therapeutic target in PC.