Background: Prostate cancer (PCa), is the second most prevalent solid tumor among men worldwide (7.3%), and the leading non-skin cancer in USA where it represents 14.9% of all new cancer cases diagnosed in 2024. This multifactorial disease exhibits substantial variation in incidence and mortality across different ethnic groups and geographic regions. Although prostate-specific antigen (PSA) remains widely used as a biomarker for PCa, its limitations reduce its effectiveness for accurate detection. Consequently, finding molecules that can either complement PSA and other biomarkers is a major goal in PCa research. Methods: Urine samples were collected from healthy donors (n = 5) and patients with low- and high-risk PCa (4 and 7 subjects, respectively) and were analyzed using proteomic data-derived systems and biology approaches. The most promising proteins were further investigated by means of The Cancer Genome Atlas (TCGA) database to assess their associations with clinical and histopathological characteristics in a larger in silico patient population. Results: By evaluating the variations in the urinary proteome as a mirror of the changes occurring in prostate tumor tissue, components of complement and coagulation cascades and glutathione metabolism emerged as hallmarks of low- and high-risk PCa patients, respectively. Moreover, our integrated approach highlighted new potential biomarkers, including CPM, KRT8, ITIH2, and RCN1. Conclusions: The good overlap of our results with what is already reported in the literature supports the new findings in the perspective of improving the knowledge on PCa. Furthermore, they increase the panel of biomarkers that could enhance PCa management. Of course, further investigations on larger patient cohorts are required.

Background: Prostate cancer (PCa) is the second most prevalent solid tumor among men globally and the leading non-skin cancer in American men. In 2020 alone, approximately 1.4 million new cases of prostate cancer were diagnosed worldwide, representing 14.1% of all new cancer cases in men. This multifactorial disease exhibits substantial variation in incidence and mortality across different ethnic groups and geographic regions. Although prostate-specific antigen (PSA) remains widely used as a biomarker for PCa, its limitations reduce its effectiveness for accurate detection. Consequently, finding biomarkers that can either complement or replace PSA is a major goal in PCa research. Methods: Urine samples were collected from healthy individuals (n=5) and patients with low- and high-risk PCa (4 and 7 subjects, respectively) and were analyzed using proteomic data-derived systems biology approaches. The most promising potential biomarkers were further investigated using The Cancer Genome Atlas (TCGA) database to assess their associations with clinical and histopathological characteristics in a larger in silico patient population. Results: In addition to describing the variations of the urinary proteome, the integration of protein profiles, network models and TCGA database has highlighted new potential biomarkers, including CPM, KRT8, ITIH2 and RCN1 that could enhance PCa management. Conclusions: Our findings support the technical feasibility of this combined approach for biomarker discovery and suggest further investigation into specific urinary proteins as potential novel biomarkers in larger patient cohorts.