The Ubiquitin-Proteasome System: A Key Regulatory Hub in Myocarditis Leading to Dilated Cardiomyopathy

The ubiquitin-proteasome system (UPS), a key regulator of protein quality control essential for maintaining normal biological processes, also plays a vital role in cardiomyopathy. Myocarditis, a myocardial inflammatory disease characterized by chronic inflammation and immune activation, can progress to secondary dilated cardiomyopathy (DCM). Inflammatory DCM is further defined by structural and functional myocardial dysfunction and immune system dysregulation. Given its role in modulating the immune system, the UPS is critical to this transition from myocarditis to DCM. This review focuses primarily on viral myocarditis, summarizing findings on the UPS's role in inflammation and its contribution to the progression to DCM in both animal models and human studies. We delve into the intricate involvement of the UPS in various processes, including virus replication, host protein degradation, pattern recognition receptor (PRR) signaling, and both innate and adaptive immunity. The molecular mechanisms underlying their context-dependent regulatory duality-wherein individual UPS components exert opposing inhibitory or activating effects across the progression from viral myocarditis to DCM-are elucidated and discussed. Targeting the UPS to ameliorate inflammation offers a potential therapeutic strategy for myocarditis and secondary DCM.