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Fowl adenovirus serotype-4 (FAdV-4) is highly lethal to poultry, making it one of the leading causes of economic losses in the poultry industry. However, a small proportion of poultry can survive after FAdV-4 infection. It is unclear whether there are genetic factors that protect chickens from FAdV-4 infection. Therefore, the livers from chickens uninfected with FAdV-4 (Normal), dead after FAdV-4 infection (Dead) or surviving after FAdV-4 infection (Survivor) were collected for RNA-seq, and 2,649 differentially expressed genes (DEGs) were identified. Among these, many immune-related cytokines and chemokines were significantly upregulated in the Dead group compared with the Survivor group, which might indicate that death is related to an excessive inflammatory immune response (cytokine storm). Subsequently, the KEGG results for DEGs specifically expressed in each comparison group indicated that cell cycle and apoptosis-related DEGs were upregulated and metabolism-related DEGs were downregulated in the Dead group, which also validated the reliability of the samples. Furthermore, GO and KEGG results showed DEGs expressed in all three groups were mainly associated with cell cycle. Among them, BRCA1, CDK1, ODC1, and MCM3 were screened as factors that might influence FAdV-4 infection. The qPCR results demonstrated that these 4 factors were not only upregulated in the Dead group but also significantly upregulated in the LMH cells after 24 h infection by FAdV-4. Moreover, interfering with BRCA1, CDK1, ODC1, and MCM3 significantly attenuated viral replication of FAdV-4. And interfering of BRCA1, CDK1, and MCM3 had more substantial hindering effects. These results provided novel insights into the molecular changes following FAdV-4 infection but also shed light on potential factors driving the survival of FAdV-4 infection in chickens., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)