PURPOSE: To explore the precise molecular by which CUEDC1, a 42 kDa protein containing a CUE domain located on chromosome 17q22, contributes to liver cancer metastasis. METHOD: CUEDC1 protein expression levels were determined in liver cancer cells using Western blot analysis. The expression of CUEDC1 in these cells was silenced through siRNA transfection Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Cell invasion and migration capabilities were evaluated using Transwell assays. The expression of transforming growth factor-beta (TGF-β)/ small mother against decapentaplegic (Smad) pathway, N-cadherin, alpha -smooth muscle actin (α-SMA), and E-cadherin was detected using Western blot. RESULT: CUEDC1 expression was found to be elevated in liver cancer cells. Knockdown of CUEDC1 reduced the expression of TGF-β, p-Smad2, and p-Smad3, key components of the TGF-β/Smad pathway. Additionally, CUEDC1 knockdown significantly decreased cell survival, migration, invasion, and the EMT process in liver cancer cells. CONCLUSION: CUEDC1 knockdown markedly reduces EMT and liver cancer cell metastasis by suppressing the TGF-β/Smad signaling pathway.