Evaluating Differential Metabolic Profiles by Prostate Cancer Risk Among Prostate Cancer Patients

<b>Background:</b> Currently there are no clinically validated biomarkers recommended for prostate cancer (PCa) risk stratification other than prostate-specific antigen (PSA). <b>Objective:</b> This study aimed to identify urine metabolites that are associated with the presence of high-grade PCa at the time of radical prostatectomy. <b>Methods:</b> Urine samples were collected from patients who underwent radical prostatectomy. High-resolution metabolomics were implemented using liquid chromatography mass spectrometry (LC-MS). To enhance metabolic feature identification, sample extracts were analyzed in two modes, C18 chromatography [reverse-phase (RP)] and hydrophilic interaction chromatography (HILIC). <b>Results:</b> This analysis included a total of 22 patients with PCa (10 high-grade and 12 low-grade) and identified 52 differential metabolites, 40 in RP and 12 in HILIC, at the <i>p</i>-value 0.05 level. Among these, methyl alpha-aspartyl phenylalaninate was most significantly differentiated, while 3-methylbutanoicacid had the largest difference (slope -3.488). In the pathway analysis, the histidine metabolism pathway was significantly enriched (<i>p</i> < 0.05) with an enrichment factor of 3.5. Although not statistically significant, alterations were also observed in the vitamin B12, B7 (biotin), B6, and B3 (niacin) pathways. <b>Conclusions:</b> These findings suggest that urinary metabolites may have the potential to differentiate high-grade from low-grade PCa. Our study also highlights the metabolic reprogramming that occurs as PCa becomes more aggressive and potential differences in dietary patterns.