Establishing AMACR as an AR-Derived Biomarker in Prostate Cancer: Metabolic and Androgen- Mediated Mechanisms

Prostate cancer (PCa) progression is primarily driven by androgen receptor (AR) signaling, which orchestrates tumor proliferation and metabolic reprogramming. Alpha-Methyl Acyl-CoA Racemase (AMACR) is a key enzyme in branched-chain fatty acid β-oxidation which is widely recognized as a diagnostic marker for PCa but its regulatory association with AR and functional implications remain unclear. Using globally available multi-omics datasets, we analyzed RNA-seq profiles from TCGA-PRAD which revealed significant overexpression of AMACR in tumors compared to normal tissues (p < 0.001). Elevated AMACR levels correlated with advanced Gleason scores, nodal positivity, and poor overall survival (p = 0.027). Functional insights from androgen stimulation and antagonism datasets, along with Chipset analyses, demonstrated direct AR occupancy at enhasssncer regions near AMACR which further confirms androgen-dependent transcriptional regulation. Protein-level evidence from immunohistochemistry and immunofluorescence supported these findings. Collectively, these results establish AMACR as an AR-regulated biomarker in PCa, implicating it in metabolic dysregulation and disease aggressiveness, and highlight its potential as a therapeutic target within the androgen-driven oncogenic network.