Abstract
The adult mammalian heart lacks the capacity to regenerate after injury, leading to heart failure. While most of the research focused on the cardiomyocyte proliferation around the infarct zones, a new study (Fan et al., Cell Stem Cell 32(1563-1576):e1511, 2025) reveals a novel mechanism in the remote endocardial zone. They identified lysozyme 2 (Lyz2) as a critical regulator, where its sustained activity in the non-regenerative hearts promotes lysosomal degradation of the extracellular matrix (ECM). Then, the breakdown of ECM was found to induce cardiomyocyte apoptosis near the endocardium. Importantly, both the genetic deletion of Lyz2 or the pharmacological inhibition of lysosomal degradation activity in mice after myocardial infarction (MI) preserved the ECM, reduced cardiomyocyte apoptosis, diminished scarring, and improved cardiac function. This work highlights LYZ2 as a novel therapeutic target for promoting heart repair in humans.