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.