A Metabolic-Related Gene Signature for Predicting Biochemical Recurrence After Radical Prostatectomy: An Integrative Analysis and Targeted Therapeutic Validation

Biochemical recurrence (BCR) after radical prostatectomy (RP) remains a major clinical challenge. Although metabolic reprogramming drives prostate cancer (PCa) progression, its predictive value for BCR and its interplay with the tumor immune microenvironment (TIME) remain incompletely understood. By integrating weighted gene co-expression network analysis (WGCNA) with machine learning, we identified four metabolic-related hub genes (GDPD1, PLA2G7, PTGDS, and SRD5A2) and developed an XGBoost-Cox model that accurately stratified BCR risk (training 5-year AUC: 0.858; validation 5-year AUC: 0.745). SHAP analysis enhanced the model's interpretability, while immunohistochemistry (IHC) validated differential protein expression of these targets across 32 clinical specimens. Furthermore, immune profiling demonstrated that these genes are closely linked to M2 macrophage-mediated immunosuppression and altered T-cell infiltration. To translate these biomarkers into therapeutic targets, we employed in silico screening, molecular docking, and molecular dynamics simulations, identifying (-)-epigallocatechin gallate (EGCG) as a promising multi-target candidate. Subsequent in vitro assays confirmed that EGCG binds stably to GDPD1, PTGDS, and SRD5A2, effectively suppressing malignant PCa phenotypes and prostate-specific antigen (PSA) secretion. In summary, we established a robust and interpretable model for predicting BCR after RP, and our in vitro validation suggests that EGCG holds promise as a therapeutic agent to delay PCa progression.