Background:　Distant　metastasis　of　colorectal　cancer　(CRC)　significantly　impacts　patient　prognosis.　Cuproptosis　is　a　new　form　of　copper　ion-dependent　cell　death.　However,　whether　cuproptosis-related　genes　(CRGs)　play　a　role　in　the　metastatic　potential　of　CRC　remains　unclear.　This　study　focuses　on　CRGs-ACAD8　to　explore　its　role　and　mechanism　in　metastatic　CRC　(mCRC).　Methods:　Clinical　sample　data　from　TCGA,　GEO,　and　Fujian　Provincial　Hospital　patients　were　integrated　to　analyze　ACAD8　expression　and　its　association　with　the　diagnosis　and　prognosis　of　CRC.　Small　interfering　RNA,　immunohistochemistry,　colony　formation,　wound-healing　assays　and　so　on　were　used　to　evaluate　the　biological　functions　of　ACAD8.　Bioinformatics　was　applied　to　investigate　its　relationships　with　immune　infiltration,　chemotherapy　sensitivity,　and　signaling　pathways.　Results:　ACAD8　expression　was　significantly　reduced　in　mCRC　and　demonstrated　excellent　diagnostic　performance.　Patients　with　high　ACAD8　expression　had　significantly　better　survival.　ACAD8　was　closely　associated　with　immune　cell　infiltration,　and　enhanced　chemotherapy　sensitivity.　Pathway　enrichment　analysis　suggested　that　ACAD8　might　inhibit　the　metastasis　of　CRC　by　regulating　pathways　such　as　response　to　metal　ions　and　tight　junction　organization.　Finally,　experiments　confirmed　a　positive　correlation　between　copper　levels　and　ACAD8　mRNA　expression,　with　CuCl2　upregulating　ACAD8　expression.　Knockdown　of　ACAD8　induced　cuproptosis.　CuCl2　inhibited　the　proliferation,　stemness,　and　migratory　abilities　of　CRC　cells,　while　si　ACAD8　attenuated　these　effects.　Moreover,　CuCl2　enhanced　the　sensitivity　of　CRC　cells　to　oxaliplatin　and　5-fluorouracil,　whereas　si　ACAD8　diminished　this　chemosensitizing　effect.　Conclusion:　As　a　novel　tumor　suppressor,　low　expression　of　CRGs-ACAD8　is　associated　with　the　metastasis　of　CRC.　ACAD8　holds　potential　diagnostic　and　prognostic　value　and　may　contribute　to　the　precise　treatment　of　CRC　by　regulating　immune　infiltration　and　chemotherapy　sensitivity.　Copyright　©　2025　Zhuang,　Chen　and　Huang.