Introduction: Prostate cancer (PCa) is one of the most common cancers among men globally. Early detection remains challenging due to the limited specificity of prostate-specific antigen (PSA) testing, which is widely used for screening and diagnosis. Emerging evidence highlights the critical role of epigenetic alterations, particularly DNA methylation and non-coding RNAs, including microRNAs and long non-coding RNAs, in PCa initiation and progression. Notably, these molecular signatures can be detected in body fluids such as blood and urine, thereby offering promising opportunities for the development of non-invasive diagnostic strategies. Methods: This systematic review was conducted in accordance with PRISMA 2020 guidelines (PROSPERO ID: CRD420251062598). PubMed, Web of Science, Cochrane Library, and Google Scholar were searched for studies published between 2015 and 2025 that evaluated epigenetic signatures in liquid biopsies for PCa detection. Eligible studies included case–control, cohort, cross-sectional, and diagnostic accuracy designs, and data on study characteristics, biomarker types, detection methods, and diagnostic performance were independently extracted. Results: Sixty-seven studies met the inclusion criteria from 5,364 screened records. These comprised 14 DNA methylation studies, 51 miRNA studies, and 2 studies with combined epigenetic signatures. Epigenetic biomarkers demonstrated consistent diagnostic potential across multiple liquid biopsy matrices, including serum, plasma, urine, and seminal fluid. GSTP1 and RASSF1A were the most frequently reported DNA methylation markers and showed moderate performance as single markers; however, multi-gene methylation panels achieved higher accuracy. In contrast, microRNAs, particularly when combined into panels, frequently exceeded PSA, especially within the diagnostic grey zone (4–10 ng/mL). miR–21, miR–141, and miR–375 were the most consistently dysregulated miRNAs, although study heterogeneity remained substantial. Overall, studies integrating methylation and miRNA markers with PSA demonstrated improved sensitivity and specificity. Conclusion: Epigenetic biomarkers detected in liquid biopsies show strong potential as non-invasive tools for early prostate cancer diagnosis. Combining DNA methylation, miRNA markers, and PSA may improve diagnostic accuracy compared with PSA alone. Future studies should prioritise standardised methods, cross-platform validation, and large multicentre cohorts. Systematic review registration: https://www.crd.york.ac.uk/prospero/ , identifier CRD420251062598.

Prostate cancer is a major cause of cancer-related deaths among men in Sub-Saharan Africa, where late-stage diagnoses are common due to limited access to affordable and sensitive diagnostic tools. Early detection is essential to improve survival and reduce the disease burden. This review explores the integration of epigenetic biomarkers and CRISPR-Cas12a technology as a transformative approach for early, non-invasive prostate cancer detection in resource-limited settings. Among the many complexities of cancer development, molecular dysregulation plays a critical role. Epigenetic modifications including DNA methylation, histone changes, and non-coding RNA expression have emerged as stable and specific biomarkers with significant potential for the early detection and characterisation of prostate carcinogenesis. However, their low concentration in body fluids poses a significant challenge for detection. CRISPR-Cas12a, renowned for its high specificity and sensitivity, offers a promising solution. When integrated with isothermal amplification and liquid biopsy techniques, it enables rapid, point-of-care diagnostics. This review proposes a CRISPR-Cas12a-based diagnostic pipeline for the detection of specific epigenetic markers in liquid biopsies that could be associated with prostate cancer. The adoption of this technology in Sub-Saharan Africa has the potential to significantly improve early diagnosis, reduce mortality, and promote health equity.