Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for severe COVID-19, but the mechanism remains unknown. This study used bioinformatics to help define the relationship between these diseases. The GSE147507 (COVID-19), GSE126848 (NAFLD), and GSE63067 (NAFLD-2) datasets were screened using the Gene Expression Omnibus. Common differentially expressed genes were then identified using a Venn diagram. Gene ontology analysis and KEGG pathway enrichment were performed on the differentially expressed genes. A protein-protein interaction network was also constructed using the STRING platform, and key genes were identified using the Cytoscape plugin. GES63067 was selected for validation of the results. Analysis of ferroptosis gene expression during the development of the 2 diseases and prediction of their upstream miRNAs and lncRNAs. In addition, transcription factors (TFs) and miRNAs related to key genes were identified. Effective drugs that act on target genes were found in the DSigDB. The GSE147507 and GSE126848 datasets were crossed to obtain 28 co-regulated genes, 22 gene ontology terms, 3 KEGG pathways, and 10 key genes. NAFLD may affect COVID-19 progression through immune function and inflammatory signaling pathways. CYBB was predicted to be a differential ferroptosis gene associated with 2 diseases, and the CYBB-hsa-miR-196a/b-5p-TUG1 regulatory axis was identified. TF-gene interactions and TF-miRNA coregulatory network were constructed successfully. A total of 10 drugs, (such as Eckol, sulfinpyrazone, and phenylbutazone) were considered as target drugs for Patients with COVID-19 and NAFLD. This study identified key gene and defined molecular mechanisms associated with the progression of COVID-19 and NAFLD. COVID-19 and NAFLD progression may regulate ferroptosis through the CYBB-hsa-miR-196a/b-5p-TUG1 axis. This study provides additional drug options for the treatment of COVID-19 combined with NAFLD disease.
