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Peer-reviewedCC BY 4.0Cells

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

  • Yilong Wang1,2
  • Jianyong Du1,2
  • Erdan Dong2,3,4,5,6,7
  • Wentao Sun2,3
7 affiliations
  1. 1NHC Key Laboratory of Cardiopulmonary Rehabilitation and Functional Recovery, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266113, China
  2. 2Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao 266071, China
  3. 3NHC Key Laboratory of Cardiopulmonary Rehabilitation and Functional Recovery, School of Medicine, University of Health and Rehabilitation Sciences, Qingdao 266113, China
  4. 4Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China
  5. 5State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
  6. 6The Institute of Cardiovascular Sciences, Peking University, Beijing 100191, China
  7. 7Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100871, China
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{wang2026lysosomal,
  title = {{Lysosomal Cathepsins in Myocardial Ischemia–Reperfusion Injury: A Druggable Nexus for Multi-Modal Cell Death}},
  author = {Yilong Wang and Jianyong Du and Erdan Dong and Wentao Sun},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15201895},
  url = {https://www.mdpi.com/2073-4409/15/20/1895},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lysosomal Cathepsins in Myocardial Ischemia–Reperfusion Injury: A Druggable Nexus for Multi-Modal Cell Death
AU  - Yilong Wang
AU  - Jianyong Du
AU  - Erdan Dong
AU  - Wentao Sun
PY  - 2026
DA  - 2026/10/17
JO  - Cells
DO  - 10.3390/cells15201895
UR  - https://www.mdpi.com/2073-4409/15/20/1895
AB  - 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.
SN  - 2073-4409
ER  -