Mechanistic insights into COVID-19 mRNA vaccine-associated myocarditis: a bioinformatics analysis

PURPOSE: While COVID-19 vaccination offers significant public health benefits, it also has potential risks, such as myocarditis. The mechanisms underlying myocarditis after COVID-19 vaccination remain poorly understood. The purpose of this study was to identify potential pathogenic genes and molecular pathways related with COVID-19 mRNA vaccine-associated myocarditis. METHODS: Differentially expressed genes (DEGs) were analyzed from a fulminant myocarditis (FM) cohort and a COVID-19 mRNA vaccination dataset. Shared DEGs were intersected, followed by functional enrichment, protein-protein interaction (PPI) network construction, and hub gene identification. Transcriptional and miRNA regulatory networks, as well as therapeutic drug predictions were also performed. RESULTS: Eighty shared DEGs were identified by interacting DEGs from the FM cohort and the vaccination cohort, we identified. Functional enrichment analysis revealed that DEGs are significantly involved in immune cell-mediated responses, highlighting the critical role of immune dysregulation. PPI network analysis revealed three hub genes (CXCR3, NKG7, and GZMH), which may be involved in the pathogenesis of vaccine-associated myocarditis. Furthermore, transcriptional networks highlighted TBX21 and STAT4 as key regulators of all hub genes, while hsa-mir-146a-5p targeted CXCR3 and NKG7. PhIP, a compound targeting CXCR3 and NKG7, emerged as a potential therapeutic candidate. CONCLUSION: This study implicates immune dysregulation driven by CXCR3, NKG7, and GZMH in post-vaccination myocarditis, supported by regulatory networks and therapeutic insights using a bioinformatics analysis. These findings advance mechanistic understanding of this rare adverse event and propose potential treatment strategy for further investigation.