Deciphering the role of circulating inflammatory proteins in myocarditis: Novel strategies for targeted therapy

AIMS: Myocarditis is closely linked to immune dysregulation, yet the causal roles of circulating inflammatory proteins in its development remain incompletely understood. This study aimed to explore whether specific inflammatory proteins are causally associated with myocarditis and to assess their potential translational relevance. METHODS: We applied a two-sample Mendelian randomization (MR) using genome-wide association studies (GWAS) summary statistics for 91 circulating inflammatory proteins and myocarditis to identify causal associations. Candidate targets were refined through differential gene expression analysis of GEO datasets, followed by enrichment and protein-protein interaction (PPI) analyses. Cell-type-specific expression was confirmed using single-cell RNA sequencing (scRNA-seq) of myocarditis tissue. Drug prediction and molecular docking analyses were performed for the key target. RESULTS: MR identified interleukin-10 receptor subunit beta (IL10RB) and leukemia inhibitory factor (LIF) as potential causal proteins for myocarditis. LIF was prioritized as a key candidate target via transcriptomics, enrichment, and PPI analysis. scRNA-seq showed high LIF expression in dendritic cells, mural cells, and fibroblasts. Drug prediction and docking evaluated its therapeutic potential. CONCLUSIONS: Elevated circulating LIF levels may be causally linked to increased myocarditis risk, supporting its potential as both a predictive biomarker and a therapeutic target. These results provide a rationale for further experimental studies to clarify the context-dependent roles of LIF in myocardial inflammation and to evaluate LIF-directed interventions.