Colorectal　cancer　is　one　of　the　most　common　malignancies　worldwide.　Liver　metastasis　is　the　major　direct　cause　of　colorectal　cancer-related　deaths.　Although　radical　resection　is　the　most　effective　treatment　for　colorectal　cancer　liver　metastasis,　several　patients　are　not　eligible　for　surgery.　Therefore,　there　is　a　need　to　develop　novel　treatments　based　on　the　understanding　of　the　biological　mechanisms　underlying　liver　metastasis　in　colorectal　cancer.　This　study　demonstrated　that　activin　A/ACVR2A　inhibits　colon　cancer　cell　migration　and　invasion,　as　well　as　suppresses　the　epithelial-to-mesenchymal　transition　of　mouse　colon　cancer　cells.　This　finding　has　been　further　validated　in　animal　experiments.　Mechanistic　studies　revealed　that　activin　A　binds　to　Smad2　(instead　of　Smad3)　and　activates　its　transcription.　Analysis　of　the　paired　clinical　samples　further　confirmed　that　the　expression　levels　of　ACVR2A　and　SMAD2　were　the　highest　in　adjacent　healthy　tissues,　followed　by　primary　colon　cancer　tissues　and　liver　metastasis　tissues,　suggesting　that　ACVR2A　downregulation　may　promote　colon　cancer　metastasis.　Bioinformatics　analysis　and　clinical　studies　demonstrated　that　ACVR2A　downregulation　was　significantly　associated　with　liver　metastasis　and　poor　disease-free　and　progression-free　survival　of　patients　with　colon　cancer.　These　results　suggest　that　the　activin　A/ACVR2A　axis　promotes　colon　cancer　metastasis　by　selectively　activating　SMAD2.　Thus,　targeting　ACVR2A　is　a　potential　novel　therapeutic　strategy　to　prevent　colon　cancer　metastasis.　©　2023　Wiley　Periodicals　LLC.