Background <p>The incidence and mortality of colorectal cancer (CRC) remain high among men, making early diagnosis a clinical priority. To distinguish colorectal cancer from colorectal polyps, this study aimed to identify cholesterol metabolism-related protein biomarkers using urinary proteomics.</p> Method <p>Urine samples were collected from male patients with colorectal cancer and colorectal polyps (CRP). LC-MS/MS-based proteomics, Western blotting, and ELISA were used to evaluate differences in urinary protein expression, and receiver operating characteristic (ROC) curve analysis was performed to assess diagnostic performance.</p> Results <p>This retrospective analysis showed that the only significant difference between patients with colorectal cancer and those with colorectal polyps was in serum high-density lipoprotein levels. Urinary proteomic analysis indicated that APOA1 expression was significantly increased in the CRC group. Western blotting and ELISA further confirmed markedly higher urinary APOA1 levels in patients with colorectal cancer. ROC curve analysis demonstrated good diagnostic performance for urinary APOA1 in distinguishing CRC from CRP, with AUC values of 0.763 and 0.881 in the discovery and validation cohorts, respectively.</p> Conclusion <p>The cholesterol metabolism-related protein APOA1 is highly overexpressed in the urine of patients with colorectal cancer and shows strong diagnostic value for differentiating colorectal cancer from colorectal polyps. Urinary APOA1 may serve as a promising noninvasive biomarker.</p> Graphical Abstract <p></p>