miRNA-mediated resistance mechanisms in prostate cancer: implications for targeted therapy and metastatic progression.

Prostate cancer (PCa) remains a leading cause of cancer-related morbidity and mortality in men, with progression to castration-resistant and metastatic disease driven largely by therapeutic resistance. While numerous reviews have cataloged dysregulated microRNAs (miRNAs) in prostate cancer, this review offers a novel, mechanism-centered synthesis focused specifically on miRNA-mediated resistance pathways across standard treatment modalities-including androgen deprivation therapy (ADT), enzalutamide, docetaxel, and radiotherapy. Rather than providing a broad survey of miRNA functions, we prioritize miRNAs with robust experimental validation in PCa (e.g., miR-21, miR-34a, miR-205, miR-141) and analyze their roles in convergent resistance mechanisms such as PI3K/AKT activation, EMT, DNA repair, and AR variant signaling. We critically evaluate the functional evidence linking these miRNAs to treatment failure, highlighting how their dysregulation promotes survival, stemness, and adaptive responses within the tumor microenvironment-particularly through extracellular vesicle (EV)-mediated communication and hypoxia-driven signaling. Although circulating miRNA signatures show promise as non-invasive biomarkers, we explicitly acknowledge major translational challenges, including poor reproducibility across cohorts, lack of standardized normalization methods, tumor heterogeneity, and inefficient in vivo delivery of miRNA-based therapeutics. This review distinguishes between well-supported preclinical findings and the current absence of clinically validated miRNA applications, emphasizing that miRNA mimics and antagomiRs remain investigational. We conclude that future progress depends on rigorous validation in prospective trials, improved delivery platforms (e.g., EV-based systems), and integration of miRNA profiles with clinical and genomic data. By focusing on resistance mechanisms rather than general dysregulation, this work provides a conceptual framework for prioritizing miRNAs with the highest potential for impacting precision oncology in prostate cancer.