Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals

Intrinsic molecular strategy at the organ level to injury stimuli remains elusive. Identifying and modulating such potential molecular strategy for systemic adaptations to injury is theoretically fascinating and therapeutically promising. Here, using integrative single-cell and spatial transcriptomic analysis, we reported that lysozyme 2 (Lyz2), a long-established myeloid marker, surprisingly indicated global injury status (across cell types and anatomic divisions) and influenced cardiac function after injury. We correlated the Lyz2 regulon of the lysosome-matrisome (particularly endocardial lysosomal-degrading Hspgs) with anatomical and functional relevance to cardiac injury and determined that such spatial model is consensus across various injury types, both mouse and human. Modulation of spatial model mediated by Lyz2 via genetic deletion or chemical inhibition in adult mice with myocardial infarction remarkably achieved immediate protective effects, a rare therapeutic benefit among current interventions for heart failure. These results provided the first molecular evidence for the unprecedented molecular strategy adopted by the heart with unparalleled therapeutic promising for organ repair.