Pharmacological inhibition of neddylation by MLN4924 protects against Coxsackievirus B3-induced myocarditis.

Viral myocarditis (VMC), predominantly caused by Coxsackievirus B3 (CVB3), remains a leading cause of sudden cardiac death and heart failure in young individuals. VMC results from both direct viral cytopathic effects and subsequent immune-mediated myocardial injury, yet effective antiviral therapies remain limited. MLN4924 (pevonedistat), a first-in-class neural precursor cell expressed developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor, has been extensively characterized for its anti-proliferative and anticancer activities, though its antiviral potential in vivo remains largely unexplored. Here, we report that pharmacological inhibition of neddylation with MLN4924 confers robust protection against CVB3-induced myocarditis in mice, significantly improving cardiac function and survival. MLN4924 treatment also markedly reduced viral replication in the heart. Mechanistically, eukaryotic translation initiation factor 4G (eIF4G) was identified as a candidate MLN4924-responsive host factor. MLN4924 attenuated the CVB3-induced loss of eIF4G protein, a change that may contribute to the suppression of CVB3 internal ribosome entry site (IRES)-driven translation and viral protein synthesis. Collectively, our findings support MLN4924 as a promising antiviral candidate for the treatment of VMC.