Abstract Background Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, the emergenceof ICI-associated myocarditis (ICI-MC) presents a severe and potentially fatal complication with poorly understood pathophysiological mechanisms. This study aimed to identify crucial immune-related genes in ICI-MC and uncover potential therapeutic targets using bioinformatics. Methods Using the GSE180045 dataset, which includes three groups—Group A: ICI patients without immune adverse events, Group B: ICI patients with non-myocarditis immune adverse events, and Group C: ICI patients with myocarditis—we analyzed differentially expressed genes (DEGs) between ICI-MC samples (Group C) and non-myocarditis controls (Groups A and B). These DEGs were then cross-referenced with 1,796 immune-related genes (IRGs) from the immPort database to identify IR-DEGs. We conducted functional enrichment analyses (GO, KEGG, GSEA), constructed a PPI network, and identified hub genes. Validation using the GSE4172 dataset led to the identification of optimal feature genes (OFGs) from the overlap between hub genes and DEGs. Predictions of target miRNAs were made, and a ceRNA network was constructed. Target drugs for hub genes were predicted using the cMAP database. Results We identified 58 DEGs between ICI-MC and controls, which led to the identification of 32 IR-DEGs after intersection with 1,796 IRGs. Functional analyses revealed enrichment in cell lysis, CD8+ T cell receptor, natural killer cell-mediated cytotoxicity, and RAGE signaling. Notably up-regulated hub genes included IL7R, PRF1, GNLY, CD3G, NKG7, GZMH, GZMB, KLRB1, KLRK1, and CD247. In the validation dataset, 407 DEGs were uncovered, resulting in the identification of 3 OFGs (KLRB1, NKG7, GZMH). The predicted target miRNAs, lincRNAs, and circRNAs constituted a comprehensive ceRNA network. Among the top 10 drugs with elevated connectivity scores was acetohydroxamic acid, indicating a need for caution in ICI treatment. Conclusion KG7, GZMH, and KLRB1 were identified as pivotal immune-related genes in ICI-MC. Biological enrichments included pathways involved in cell lysis, the CD8+ T cell receptor pathway, natural killer cell-mediated cytotoxicity, RAGE signaling, and proinflammatory responses. The ceRNA network illuminated the role of critical molecules and underscored the importance of avoiding drugs such as acetohydroxamic acid in ICI treatment.The flowchart of this study ceRNA network
Zhang et al. (Sat,) studied this question.