The Personalized Medicine Revolution in Castration-Resistant Prostate Cancer (CRPC): Connecting Epigenetic Landscapes with AI‑Driven RNA Therapeutic Strategies

Castration-resistant prostate cancer (CRPC) escapes cure despite successive generations of androgen-receptor inhibitors and radiopharmaceuticals. A review of English-language studies published between January 2019 and June 2025 examined epigenetic deregulation, RNA therapeutics, and AI tools. DNA methylation at tumor-suppressor promoters (GSTP1, RASSF1A), histone modifications mediated by EZH2, and enhancer rewiring by pioneer factors such as GATA2 drive resistance and lineage plasticity. RNA modalities, including antisense oligonucleotides targeting the androgen receptor, small interfering RNAs directed at AR splice variants (AR-V7), and self-adjuvanted mRNA vaccines encoding PSA/PSMA/STEAP1, showed preclinical and early clinical activity. AI platforms employing random forests, autoencoders, and generative models integrate multi-omics data to identify combinatorial biomarkers, while machine-learning-guided lipid-nanoparticle design accelerates delivery optimization. These advances position CRPC management for a shift from broad androgen-axis suppression toward stratified, mechanism-based therapies. Realizing this potential requires multidisciplinary collaboration, regulatory adaptation, and deliberate attention to health equity.