MicroRNAs in prostate cancer radioresistance: mechanisms, target-based network analysis and translational opportunities

BACKGROUND: Prostate cancer (PC) is a global major health concern, and radiotherapy is part of the standard treatment for locally advanced disease. Despite medical advances, the effectiveness of this therapy is often compromised by radiation resistance, a complex and adaptive process that allows tumor recurrence and progression. MicroRNAs (miRNAs) have emerged as key regulators of radiation response, influencing DNA repair, apoptosis, and survival signaling. These molecules actively contribute to radiation resistance acquisition and mediate dynamic interactions within the tumor ecosystem. METHODS: This review analyzes the molecular basis of radiation resistance in PC, focusing on miRNAs with experimental evidence of involvement in PC radiation response. A structured literature search was performed to identify original studies investigating the role of miRNAs in PC radioresistance. RESULTS: Radiation resistance is mediated by the coordination of various mechanisms, including DNA damage repair, pro-survival signaling, adaptation to oxidative stress, metabolic reprogramming, and phenotypic plasticity, such as epithelial-mesenchymal transition and cancer stem cell-like states. Through a structured analysis of 17 studies, we identified the main miRNAs associated with radioresistance, and their experimentally validated targets showed convergence in shared signaling pathways, including the FOXO pathways. CONCLUSIONS: miRNAs represent candidate biomarkers and therapeutic targets for PC radioresponse; however, their predictive value for radiotherapy response requires prospective clinical validation. miRNAs are key regulators of PC radioresistance, while their validated targets converge within shared molecular networks, supporting their potential as candidate biomarkers and therapeutic targets for future precision radiotherapy strategies. Emerging evidence also suggests that extracellular vesicle-derived miRNAs may contribute to intercellular communication of resistance phenotypes, warranting future investigation.