Cellular protein quality control in viral myocarditis: molecular mechanisms and therapeutic implication

SUMMARY Viral myocarditis, an inflammatory disease of the myocardium caused by viral infections, poses a significant global health concern, particularly in young adults and children. This condition often progresses to dilated cardiomyopathy and heart failure, underscoring the urgent need for a deeper understanding of its underlying mechanisms. Central to its pathogenesis is the disruption of protein quality control (PQC) system, which is essential for maintaining cardiac proteostasis under both physiological and pathological conditions. This system, comprising molecular chaperones, the ubiquitin-proteasome system, and autophagy pathways, collectively ensures cellular homeostasis. In viral myocarditis, viral replication and host immune responses impose substantial stress on cardiomyocytes, overwhelming the PQC mechanisms. Consequently, misfolded and aggregated proteins, as well as damaged organelles, accumulate, further aggravating myocardial injury. Notably, while PQC pathways play a critical role in limiting viral replication and protecting cardiomyocytes, viruses can subvert these systems to enhance their own replication and provoke maladaptive responses, thereby worsening cardiac injury. This review summarizes current knowledge on the complex interplay between PQC system and viral myocarditis, highlights key knowledge gaps, and discusses potential therapeutic strategies to preserve cardiac function and improve clinical outcomes.