Epigenetic and Liquid Biopsy Biomarkers in Prostate Cancer: Bridging Tumor Heterogeneity and Clinical Implementation.

Prostate cancer (PCa) is the most common malignancy in men, characterized by significant genetic and epigenetic heterogeneity, which complicates both diagnosis and treatment processes. Epigenetic mechanisms-including DNA methylation, chromatin remodeling, and dysregulated non-coding RNAs (miRNAs, lncRNAs, circRNAs)-contribute to tumor initiation, progression, and therapy resistance, offering promising diagnostic and prognostic biomarker opportunities. Liquid biopsy technologies, such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes, allow minimally invasive, real-time monitoring of tumor evolution and resistance mechanisms, complementing traditional biomarkers like PSA and supporting precision oncology approaches. Clinically implemented assays, including PCA3, ConfirmMDx, and ExoDx Prostate, along with emerging multi-analyte panels, enhance risk stratification, reduce unnecessary biopsies, and guide therapeutic decisions. Integration of epigenetic and liquid biopsy biomarkers into multimodal diagnostic pathways has the potential to support personalized management of prostate cancer; however, many still require further validation and optimization.