Porcine epidemic diarrhea virus (PEDV) poses a significant threat to the global swine industry; however, the host factors that support its replication remain poorly understood. Our previous study showed that myeloid cell leukemia 1 (MCL1) is a pro-PEDV replication cellular factor through genome-scale CRISPR-Cas9-knockout (KO) screening. Nevertheless, the molecular mechanism whereby MCL1 promotes PEDV replication is unclear. In this study, we first demonstrated that MCL1 promotes PEDV replication