###### Abstract  
Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. _Objective_: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. _Methods_: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). _Results_: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (\(\geq\)5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression.  
More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein-protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblast morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic outstaride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. _Conclusion_: These data provide proof of concept that re-reprogramming of testosterone metabolism through \"SRD5A1 withdrawal\" or \"SHBG induction\" is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.  
prostate cancer; HSD17B2; HSD17B3; SHBG and SRD5A1; advanced disease; castration-resistance; therapy resistance; testosterone metabolism; androgenic reprogramming