LDLR-OPN Interaction Drives COVID-19 Myocarditis Through Monocyte Recruitment.

COVID-19-associated myocarditis is marked by macrophage-rich inflammation and adverse cardiac outcomes, yet its mechanisms remain unclear. We developed a reproducible BSL-2 mouse model by combining cardiac-specific human low-density lipoprotein receptor (LDLR) overexpression (AAV9-cTnT-hLDLR) with chimeric SARS-CoV-2 infection in keratin 18 human angiotensin-converting enzyme 2 transgenic mice, achieving 100% penetrance of macrophage-predominant myocarditis with cardiomyocyte necrosis and gasdermin D-mediated pyroptosis. We identified a previously unrecognized high-affinity interaction between LDLR (CR2-CR5 domains) and osteopontin that drives monocyte recruitment. Induced degrader of LDLR-mediated LDLR degradation completely abrogated myocarditis, while dimethyl fumarate significantly reduced pyroptosis and inflammatory burden. Importantly, human myocarditis autopsy hearts exhibited >10-fold up-regulation of LDLR and intercellular adhesion molecule-1, mirroring the murine findings. These data establish the LDLR-osteopontin axis as a mechanistic and targetable driver of COVID-19 myocarditis and provide a translational platform for therapeutic development in viral myocarditis.