Soluble ST2 drives fulminant myocarditis progression via the IGF2R-YY1 mitochondrial axis

Fulminant myocarditis (FM) is a life-threatening inflammatory cardiomyopathy with high mortality. Soluble ST2 (sST2), traditionally regarded as a decoy receptor for interleukin-33 (IL-33), is markedly elevated in FM, yet its mechanistic and translational roles remain unclear.

A Coxsackievirus B3-induced FM mouse model was used to define the cellular source and function of sST2 through histological, molecular, and integrated single-cell and single-nucleus transcriptomic analyses. Cardiomyocyte responses were assessed in neonatal murine cardiomyocytes and human engineered heart tissues. The therapeutic efficacy and safety of sST2-neutralizing antibodies were evaluated in vivo, with clinical relevance examined in a cohort of FM patients.

sST2 originated predominantly from infiltrating CCR2+ macrophages in FM hearts and aggravated cardiac damage by amplifying inflammation, mitochondrial dysfunction, and contractile failure. Mechanistically, sST2 acted independently of IL-33. It entered cardiomyocytes via IGF2R and bound the transcription factor YY1, preventing its nuclear translocation and repressing mitochondrial electron transport chain gene expression, thereby reducing ATP synthesis. Neutralizing antibodies targeting sST2 effectively restored mitochondrial function, improved hemodynamics, and reduced mortality without evident short-term systemic toxicity. Integrated single-cell and single-nucleus transcriptomic analyses revealed broad therapeutic effects across cardiomyocytes, fibroblasts, endothelial cells, and macrophages. Combined glucocorticoid and anti-sST2 therapy provided additive benefit. Clinically, elevated plasma sST2 independently predicted 30-day mortality or extracorporeal membrane oxygenation requirement in FM patients, outperforming N-terminal pro-B-type natriuretic peptide and cardiac troponin I for prognostic discrimination.

sST2 drives FM by disrupting cardiomyocyte mitochondrial homeostasis independently of IL-33 and represents both a clinically prognostic biomarker and a therapeutic target.