Simple SummaryThe present work aims to shed light on the role that Transcription Factors (TFs) play in the alteration of gene expression and regulation driven by COVID-19 infection. In this regard, 19 human transcription factors were selected, since they are predicted to target and potentially regulate human proteins interacting with Spike glycoprotein of SARS-CoV-2. Thirty-one human genes, predicted as targets of these TFs, were selected since they showed statistically significant differences in their correlation values with respect to TFs between healthy and COVID-19 patients. It can be hypothesised that they are major players in the alteration of the regulation pattern driven by COVID-19. In this light, together with the 19 identified TFs, the 31 human genes be considered as potential targets to counteract COVID-19 infection.AbstractSARS-CoV-2 and its many variants have caused a worldwide emergency. Host cells colonised by SARS-CoV-2 present a significantly different gene expression landscape. As expected, this is particularly true for genes that directly interact with virus proteins. Thus, understanding the role that transcription factors can play in driving differential regulation in patients affected by COVID-19 is a focal point to unveil virus infection. In this regard, we have identified 19 transcription factors which are predicted to target human proteins interacting with Spike glycoprotein of SARS-CoV-2. Transcriptomics RNA-Seq data derived from 13 human organs are used to analyse expression correlation between identified transcription factors and related target genes in both COVID-19 patients and healthy individuals. This resulted in the identification of transcription factors showing the most relevant impact in terms of most evident differential correlation between COVID-19 patients and healthy individuals. This analysis has also identified five organs such as the blood, heart, lung, nasopharynx and respiratory tract in which a major effect of differential regulation mediated by transcription factors is observed. These organs are also known to be affected by COVID-19, thereby providing consistency to our analysis. Furthermore, 31 key human genes differentially regulated by the transcription factors in the five organs are identified and the corresponding KEGG pathways and GO enrichment are also reported. Finally, the drugs targeting those 31 genes are also put forth. This in silico study explores the effects of transcription factors on human genes interacting with Spike glycoprotein of SARS-CoV-2 and intends to provide new insights to inhibit the virus infection.