BACKGROUND We sought to further our understanding of the biological characteristics underlying severe COVID-19. MATERIAL AND METHODS RNA sequencing (RNA-Seq) analysis was used to evaluate peripheral blood mononuclear cells from 4 patients with severe COVID-19 and 4 healthy controls. We performed gene expression analyses to detect differentially expressed genes (DEGs). Enrichment analyses were performed to identify their molecular processes and signaling pathways, and the protein-protein interaction network was constructed to extract the core gene cluster. The investigation of protein-chemical interactions and regulatory signatures for specific regulatory checkpoints and powerful chemical agents was then conducted for these essential genes. Finally, we used single-cell RNA-Seq analysis from an online platform to show how these genes were expressed differently, depending on the kind of cell. RESULTS A total of 268 DEGs were found. The biological process of protein ubiquitination was later discovered to be highly influenced by the core gene cluster (ITCH, TRIM21, RNF130, FBXO11, UBE2J1, and ASB16) at the transcriptome level. Six transcription factors, FNIC, FOXA1, YY1, GATA2, MET2A, and FOXC1, as well as miRNAs hsa-miR-1-3p and hsa-miR-27a-3p were identified. We found a potent chemical agent, copper sulfate, may regulate protein ubiquitination genes cooperatively, and the genes regulating protein ubiquitination could be expressed highly on the macrophages. CONCLUSIONS Taken together, we suggest that protein ubiquitination is a crucial functional process in patients with severe COVID-19. This study will give a deeper insight into biological characteristics and progression of COVID-19 and facilitate development of novel therapeutics, leading to significant advancements in the COVID-19 pandemic.