This　study　explores　and　verifies　potential　molecular　targets　through　which　KRAS　mutations　regulate　the　colonization　of　Fusobacterium　nucleatum　(FN)　in　colorectal　cancer　(CRC).　This　study　combined　multiple　bioinformatics　methods　and　biological　assays.　Through　The　Cancer　Genome　Atlas,　Gene　Expression　Omnibus,　Human　Protein　Atlas,　immunohistochemistry,　and　co-culture　assays,　we　further　confirmed　the　differential　expression　of　SERTAD4　in　CRC.　We　delved　deeper　into　examining　how　expression　of　SERTAD4　is　linked　with　immune　cell　infiltration　and　the　enrichment　of　potential　pathways.　Lastly,　through　bacterial　phenotypic　assays,　we　validated　the　function　of　SERTAD4.　As　a　molecule　associated　with　KRAS　mutations　and　FN　infection,　the　expression　levels　of　SERTAD4　were　downregulated　in　CRC.　The　diagnostic　efficacy　of　SERTAD4　for　CRC　is　not　inferior　to　that　of　CEA.　Low　expression　of　SERTAD4　is　associated　with　poorer　overall　survival　in　CRC.　Correlation　analysis　found　that　increased　expression　of　SERTAD4　is　associated　with　various　immune　cell　infiltrations　and　immune　checkpoint　genes.　Finally,　bacterial　adhesion　and　invasion　assays　verify　that　SERTAD4　inhibits　the　adhesion　and　invasion　abilities　of　FN　in　CRC.　This　study　demonstrates　that　SERTAD4　exerts　a　protective　role　in　CRC　by　inhibiting　the　colonization　of　FN.　©　2024　The　Author(s).　Journal　of　Cellular　and　Molecular　Medicine　published　by　Foundation　for　Cellular　and　Molecular　Medicine　and　John　Wiley　&　Sons　Ltd.