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NFX1-123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1-123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1-123 expression in 24 cancers compared with normal tissues. The NFX1-123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their effects on NFX1-123-related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1-123 expression, with nine having had greater NFX1-123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three-dimensional structure of NFX1-123, and drug libraries were screened for high-binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from -1.3 to -10 Kcal/mol were identified. The top four compounds were used to treat HPV- and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1-123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1-123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1-123 a potential novel therapeutic target., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)