Soluble ST2-associated protein induces cardiac injury by inhibiting mitochondrial ETC gene expression in cardiomyocytes in fulminant myocarditis

Abstract Background Fulminant myocarditis (FM) is a severe and life-threatening inflammatory cardiac disease characterized by rapid progression and high mortality. Despite advances in life support-based treatments, targeted therapies for FM remain lacking. Previous soluble growth stimulation-expressed gene 2 (sST2), sST2-associated isoform (sST2A), has been identified as a sensitive and specific biomarker for FM; however, its functional role and underlying mechanisms in FM pathogenesis remain unclear. Methods FM was induced in A/J mice via intraperitoneal injection of Coxsackievirus B3 (CVB3). Recombinant sST2A protein was administered to evaluate its effects on cardiac function and inflammation. Transcriptomic analyses and mechanistic studies were conducted to uncover the role of sST2A in FM pathogenesis. Additionally, the therapeutic potential of sST2A-neutralizing antibodies was evaluated. Results sST2 levels were significantly elevated in the plasma and heart tissue of FM mice, with C-C motif chemokine receptor 2+ (CCR2+) macrophages identified as the primary cellular source, and its secretion was mediated by a Ca²⁺-dependent mechanism. Recombinant sST2A administration exacerbated cardiac injury, inflammation, and dysfunction in FM mice and induced contractile dysfunction in engineered human heart tissue. Mechanistically, sST2A entered cardiomyocytes via clathrin-mediated endocytosis and interacted with the transcription factor YY1 in the cytoplasm. This interaction prevented YY1 nuclear translocation, suppressing mitochondrial ETC gene expression, impairing ATP production, and causing cardiomyocyte contractile dysfunction, revealing a novel, non-canonical mechanism by which sST2A regulates mitochondrial function. Importantly, neutralization of sST2A with specific antibodies significantly reduced cardiac inflammation, restored mitochondrial function, improved cardiac contractility, and decreased mortality in FM mice. Conclusions This study identifies sST2A as a critical pathogenic factor in FM, elucidates its novel role in modulating mitochondrial function through a non-classical mechanism, and validates the therapeutic potential of sST2A-neutralizing antibodies. These findings provide a strong foundation for targeting sST2A as a promising therapeutic strategy for FM and other inflammatory cardiac diseases.