Abstract
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 cardiacspecific 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. (JACC Basic Transl Sci. 2026;11:101553) © 2026 The Authors. Published by Elsevier on behalf ofthe American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).