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Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate\u2010limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT\u2010qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non\u2010PM primary tumors. Here, we showed that cancer\u2010associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture\u2010induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFs<jats:italic><jats:sup>CPT1A<\/jats:sup><\/jats:italic><jats:sup>\u2010OE<\/jats:sup> <jats:italic>in vitro<\/jats:italic> and impaired the survival and growth of organoids derived from CRC\u2010PM. Finally, we found that directly blocking FAO in CAFs<jats:italic><jats:sup>CPT1A<\/jats:sup><\/jats:italic><jats:sup>\u2010OE<\/jats:sup> with etomoxir inhibits migration and invasion <jats:italic>in vitro<\/jats:italic> and decreases tumor growth and intraperitoneal dissemination <jats:italic>in vivo<\/jats:italic>, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF\u2010induced colorectal cancer with peritoneal dissemination\/metastases.<\/jats:p>","DOI":"10.1002\/1878-0261.12917","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T02:30:18Z","timestamp":1612578618000},"page":"1391-1411","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":105,"title":["Enhancing cancer\u2010associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5489-4869","authenticated-orcid":false,"given":"Shaoyong","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Colon and Rectum Surgery The Sixth Affiliated Hospital (Guangdong Gastrointestinal and Anal Hospital) 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