Soluble ST2 induces cardiac contractile dysfunction by repressing mitochondrial electron transport chain genes in cardiomyocytes during fulminant myocarditis

Fulminant myocarditis (FM) is an acute fatal disease characterised by myocardial inflammation. Our previous study identified soluble growth stimulation- expressed gene 2 (sST2) as a sensitive and specific biomarker for early diagnosis of FM. However, its function in FM remains unclear.In the present study, we observed a marked elevation of sST2 in the plasma and hearts of mice with FM induced by coxsackievirus B3 (CVB3) and explored the main cellular sources of sST2 in FM. Moreover, using recombinant sST2 protein administration and unbiased transcriptomics analyses, we investigated the role and underlying mechanisms of sST2 in FM. Importantly, we found that sST2 has a novel non-classical function in cardiomyocytes, other than acting as an IL-33 decoy receptor. These findings reveal a novel role and action mechanism of sST2 in FM and suggest that sST2 may be a potential therapeutic target for FM. To explore how sST2 aggravates cardiac deterioration in mice and how sST2 induces contractile dysfunction in cardiomyocytes, RNA sequencing was performed on the hearts of mice with FM and cultured primary neonatal mouse cardiomyocytes (NMCMs) infected with CVB3 Transcriptome sequencing was performed on the hearts of CVB3-induced FM and normal control mice. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the upregulated differentially expressed genes (DEGs), the chemokine signalling pathway was significantly enriched To identify whether the potential target genes were directly regulated by YY1 in NMCMs and affected by sST2 treatment, we integrated the DEGs from NMCM RNA-seq with or without sST2 treatment with YY1-binding genes identified by YY1 CUT&Tag-seq