Myocarditis is a heterogeneous inflammatory disease of the heart muscle mainly caused by viral infection and contributes to 42% of all sudden deaths in young adults annually. Viral myocarditis causes myocyte dysfunction and severe cardiac inflammation and likely results from an adverse immune response to cardiotropic viruses, such as enterovirus coxsackievirus B3 (CVB3) as well as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus cause of ongoing coronavirus disease 19(COVID-19) pandemic. The exact pathophysiology mechanisms are unknown and effective therapies are still lacking for treating myocarditis. Here, we aim to develop a therapeutic approach for treating viral myocarditis. Our strong preliminary data and publication show that: 1) the E3 ligase TRIM18 promotes pathogenesis of CVB3-induced viral myocarditis by dampening antiviral type I interferon (IFN) response and promoting CVB3-induced adverse immune response; 2) TRIM18 is significantly upregulated in the hearts from patients with viral myocarditis and is induced by SARS-CoV infection; 3) TRIM18 is highly induced by cardiotropic virus CVB3 in cardiomyocytes, whereas knockdown of super-enhancers (SEs) transcriptional coactivator bromodomain containing protein-4 (BRD4) significantly reduces TRIM18 expression, indicating BRD4-mediated SEs may highly drive TRIM18 induction in cardiomyocytes; 4) the BRD4 inhibitor INCB054329 reduces expression of the critical regulator TRIM18 and restricts CVB3 replication in cardiomyocytes. Based on our strong preliminary data and publication, the central hypothesis to be tested is that BRD4-mediated SEs drive TRIM18 to suppress antiviral type I IFN response for causing viral myocarditis, while BRD4 inhibitor INCB054329 controls viral myocarditis by reducing TRIM18 expression and rescuing viral induced adverse immune response. We will test this hypothesis using two aims. Aim 1 will determine pathological relevance and molecular mechanisms of BRD4-mediated TRIM18 expression in causing viral myocarditis. Aim 2 will test a therapeutic approach by targeting TRIM18 for treating viral myocarditis. Successful completion of this high risk-high reward study will provide the first in vivo evidence for direct association of TRIM18 driven by BRD4-mediated SEs with pathogenesis of viral myocarditis. Results from these studies might identify TRIM18 as a promising therapeutic target in the treatment of viral myocarditis and associated cardiovascular diseases.