Lysosomal Cathepsins in Myocardial Ischemia-Reperfusion Injury: A Druggable Nexus for Multi-Modal Cell Death

Myocardial ischemia-reperfusion injury (MIRI) remains a central challenge in coronary artery disease. Timely revascularization salvages ischemic myocardium yet simultaneously triggers cardiomyocyte death that offsets therapeutic benefit. Apoptosis, necroptosis, pyroptosis, and ferroptosis are all executed during ischemia-reperfusion, yet their temporal coordination and inter-regulation remain incompletely understood. Consequently, monotherapies targeting single death pathways have repeatedly failed in clinical translation. This review examines the pharmacological evidence that cathepsin-driven lysosomal membrane permeabilization (LMP) operates as a proteolytic nexus coordinating these death programs. Cytosolic cathepsins cleave Bid to amplify mitochondrial apoptosis, bind and activate the NOD-like receptor protein 3 (NLRP3) inflammasome to drive pyroptosis, and degrade ferritin to mobilize iron for ferroptosis, while participating in PANoptotic execution. In endothelial cells, the same machinery promotes microvascular obstruction and no-reflow. We further evaluate circulating cathepsins and death-pathway biomarkers for patient stratification and appraise isoform-selective inhibitors, multi-target nanomedicine, and biomarker-guided adaptive trial designs. Positioning the lysosomal-cathepsin axis as an upstream druggable node provides a mechanistic rationale for simultaneous multi-target cardioprotection and a route to mechanism-matched pharmacology in ischemic heart disease.