The novel contributions of our research are: 1) utilization of multiple mouse strains to identify a key regulator of inflammation across various myocarditis subtypes; 2) the elevated expression of OPN was observed in the early stage of acute viral myocarditis mice and patients with myocarditis; 3) the elevation of OPN in myocarditis was primarily originated from macrophages; 4) conditional knockout of OPN in macrophages prevented virus-induced cardiac injury; 5) STAT4-induced OPN increased IL-12 production, which in turn activated STAT4, generating a pro-inflammatory loop. The gene discussed is STAT4; the disease is myocarditis.