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Prostate cancer (PCa) cells display abnormal expression of proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown the anti-tumoral role of heme oxygenase 1 (HO-1) in this disease. In this work, we undertook a mass spectrometry-based proteomics study to identify HO-1 molecular interactors that might collaborate with its modulatory function in PCa. Among the HO-1 interactors, we identified proteins with nuclear localization. Correlation analyses, using the PCa GSE70770 dataset, showed a significant and positive correlation between <i>HMOX1</i> and 6 of those genes. Alternatively, <i>HMOX1</i> and <i>YWHAZ</i> showed a negative correlation. Univariable analyses evidenced that high expression of <i>HNRNPA2B1, HSPB1, NPM1, DDB1, HMGA1, ZC3HAV1,</i> and <i>HMOX1</i> was associated with increased relapse-free survival (RFS) in PCa patients. Further, PCa patients with high <i>HSPB1/HMOX1</i>, <i>DDB1/HMOX1</i>, and <i>YWHAZ/HMOX1</i> showed a worse RFS compared with patients with lower ratios. Moreover, a decrease in RFS for patients with higher scores of this signature was observed using a prognostic risk score model. However, the only factor significantly associated with a higher risk of relapse was high <i>YWHAZ</i>. Multivariable analyses confirmed <i>HSPB1</i>, <i>DDB1</i>, and <i>YWHAZ</i> independence from PCa clinic-pathological parameters. In parallel, co-immunoprecipitation analysis in PCa cells ascertained HO-1/14-3-3ζ/δ (protein encoded by <i>YWHAZ</i>) interaction. Herein, we describe a novel protein interaction between HO-1 and 14-3-3ζ/δ in PCa and highlight these factors as potential therapeutic targets.