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The aim of this study was to investigate the effects of proline metabolism\u2010related genes and exogenous proline on the progression of colorectal cancer (CRC). We aimed to further clarify the role of pyrroline\u20105\u2010carboxylate reductase (PYCR) 2, a key enzyme of proline synthesis, in the regulation of colorectal intraperitoneal metastatic tumors. This study was carried out based on The Cancer Genome Atlas (TCGA) data, database analysis, single\u2010cell functional analysis, tissue microarray, cell experiments, and animal models. We found that, PYCR2 mRNA and protein levels were upregulated in CRC. The mRNA level of PYCR2 was closely related to the prognosis and tumor metastasis of CRC patients. The upregulated PYCR2 expression was at least partly due to low promoter methylation levels. The nomogram constructed based on PYCR2 expression and clinical characteristics of CRC showed good accuracy in predicting lymph node metastasis. Pycr2 knockdown inhibited epithelial\u2013mesenchymal transition (EMT) of mouse CRC cells. Proline supplementation did not rescue the inhibition of mouse CRC cell proliferation and migration by Pycr2 knockdown. Proline supplementation also did not rescue the suppression of subcutaneous tumors and intraperitoneal metastatic tumors in mice by Pycr2 knockdown. PYCR2 co\u2010expressed genes in TCGA\u2010CRC were enriched in epigenetic modification\u2010related biological processes and molecular functions. Four small molecules with the lowest binding energy to the PYCR2 protein were identified. Collectively, Pycr2 knockdown inhibited mouse CRC progression in a proline\u2010independent approach. PYCR2 may be a promising tumor metastasis predictor and therapeutic target in CRC.<\/jats:p>","DOI":"10.1111\/cas.15635","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T09:23:35Z","timestamp":1667035415000},"page":"908-920","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting <scp>PYCR2<\/scp> inhibits intraperitoneal metastatic tumors of mouse colorectal cancer in a proline\u2010independent approach"],"prefix":"10.1111","volume":"114","author":[{"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Nankai Hospital Tianjin Medical University  Tianjin China"},{"name":"Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases Tianjin Nankai Hospital  Tianjin 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