DEAD-Box Helicase 5(DDX5), also known as P68, is one of the founding members of the DEAD-Box helicase superfamily and it plays a key role in RNA metabolism. Several studies have reported that DDX5 is involved in many types of tumors through abnormal expression, but the detailed mechanism of DDX5 in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we demonstrate that the level of DDX5 is a negative prognostic factor for ESCC. The obtained results indicated that decreased expression of DDX5 inhibits ESCC cell proliferation and metastasis. Further experiments suggested that CDK2, Cyclin D1 and Vimentin were downregulated, while E-cadherin was upregulated after DDX5 was knocked down. In addition, DDX5 was positively correlated with the expression of BIP, phospho-eIF2a, phospho-PERK and P62, suggesting that knockdown of DDX5 can inhibit endoplasmic reticulum(ER) stress and promote the recovery of autophagy flux. Therefore, this study demonstrates that the downregulation of DDX5 in ESSC correlates to lower malignancy and presents a novel target for the development of new treatment strategies. (C) 2020 Elsevier Inc. All rights reserved.