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

Summary

Soluble ST2, released predominantly from CCR2+ macrophages in fulminant myocarditis, enters cardiomyocytes via IGF2R and binds YY1, blocking its nuclear translocation and repressing mitochondrial electron transport chain genes, thereby impairing ATP synthesis. Neutralizing sST2 restored mitochondrial function, improved hemodynamics, reduced mortality in vivo, and plasma sST2 outperformed NT-proBNP and troponin I for short-term prognostication.

Key Findings

• sST2 originates mainly from infiltrating CCR2+ macrophages in fulminant myocarditis and worsens inflammation, mitochondrial dysfunction, and contractile failure.
• Mechanistically, sST2 enters cardiomyocytes via IGF2R and binds YY1, preventing its nuclear translocation and repressing mitochondrial ETC gene expression, reducing ATP.
• sST2-neutralizing antibodies restored mitochondrial function, improved hemodynamics, and reduced mortality in vivo; plasma sST2 independently predicted 30-day mortality/ECMO and outperformed NT-proBNP and cTnI.

Clinical Implications

Plasma sST2 can aid early risk stratification in fulminant myocarditis and guide aggressive supportive care. Therapeutic sST2 neutralization, potentially combined with glucocorticoids, warrants clinical trials as a targeted immunomodulatory strategy.

Limitations

• Predominantly preclinical; human interventional data are lacking
• Long-term safety and immunogenicity of sST2 neutralization remain to be established

Future Directions

Prospective trials testing anti-sST2 therapy in fulminant myocarditis, validation of sST2 risk thresholds, and exploration of combinatorial immunomodulation (e.g., with glucocorticoids).