Background: Since December 2019, Coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. There is an increased risk of ischemic stroke (IS) associated with COVID-19. However, few studies have been reported to explain the potential correlation between COVID-19 and IS.

Methods: We investigated the relationship and relevant mechanisms between COVID-19 and IS using single-cell RNA sequencing and multiple bioinformatics approaches.

Results: By intersecting differentially expressed genes and WGCNA critical module genes, we obtained 73 COVID-19-related IS genes. According to the KEGG pathway analysis, the COVID-19-related IS disease genes were significantly enriched in the hematopoietic cell lineage pathway, ribosome pathway, COVID-19 pathway and primary immunodeficiency pathway. Finally, three genes associated with immunity (B4GALT5, CRISPLD2, F5) and two genes associated with ferroptosis (ACSL1, CREB5) were identified up-regulated in COVID-19-related IS. Significantly, it was found that all five genes were highly expressed in monocytes by single cell RNA sequencing.

Conclusion: We believe these genes (B4GALT5, CRISPLD2, F5, ACSL1, CREB5) may regulate the immune response and ferroptosis of multiple immune cells, mainly including monocytes, which may contribute to the development of COVID-19-related IS. In addition, these genes may be potential targets for the treatment of COVID-19-related IS.