Kuzuoglu-Ozturk et al. showcase a therapeutic approach, “translatome therapy,” to combat lethal prostate cancer. Zotatifin, a clinical molecule, targets the RNA-helicase eIF4A. Zotatifin decreases the select translation of key oncogenes, androgen receptor (AR), and HIF1α through remodeling their 5′ UTR RNA structure. Zotatifin enhances anti-androgen and radiotherapy sensitivity, highlighting a promising anti-cancer treatment.