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

Q: What is the clinical evidence from this study?

Study design: Review. Population: Myocardial ischemia-reperfusion injury (MIRI) in coronary artery disease. Intervention: Isoform-selective cathepsin inhibitors, multi-target nanomedicine, and downstream cell death pathway modulators.

Yi Wang; Jianyong Du; Erdan Dong; Wentao Sun

doi:10.3390/cells15201895

October 17, 2026CellsOpen Access

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

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Key result

Cathepsin-driven lysosomal permeabilization coordinates multiple cell death pathways in myocardial ischemia-reperfusion injury.

Why the study?

The temporal coordination and inter-regulation of apoptosis, necroptosis, pyroptosis, and ferroptosis during myocardial ischemia-reperfusion injury remain incompletely understood, and monotherapies targeting single death pathways have repeatedly failed in clinical translation.

Key Points

To review the pharmacological and translational evidence that cathepsin-driven lysosomal membrane permeabilization coordinates multiple cell death programs during myocardial ischemia-reperfusion injury.
Narrative synthesis of preclinical cellular, isolated-heart, and animal models alongside clinical biomarker studies investigating lysosomal membrane permeabilization in myocardial ischemia-reperfusion.
Evaluated structural data on inflammasome interfaces, organelle-specific iron dynamics in ferroptosis, and outcomes from recent anti-inflammatory clinical trials including CANTOS and CLEAR SYNERGY.
Lysosomal membrane permeabilization releases cytosolic cathepsins such as CTSB, which cleave Bid to amplify apoptosis, activate NLRP3 to drive pyroptosis, and degrade ferritin to trigger ferroptosis.
Cathepsin-dependent NLRP3 inflammasome and GSDMD activation in endothelial cells compromises microvascular barrier integrity, correlating with post-PCI microvascular obstruction and intramyocardial hemorrhage within 48 h.
Cell death biomarkers demonstrate prognostic value in prospective cohorts, including serum IL-1β predicting no-reflow with an AUC of 0.745, supporting mechanism-matched patient stratification over broad monotherapies.

Structured PICO

P

Population

Preclinical cellular, rodent, and large-animal models of myocardial ischemia-reperfusion injury (MIRI) and clinical cohorts with acute coronary syndrome / ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI)

I

Intervention

Pharmacological or genetic modulation of the lysosomal-cathepsin axis and downstream cell death pathways (including broad-spectrum cysteine protease inhibitors like E64d, CTSB inhibitor CA-074Me, CTSL inhibitor CAA0225, NLRP3 inhibitors MCC950 and dapansutrile, ferroptosis inhibitors ferrostatin-1 and UAMC-3203, and targeted nanoparticles)

Positioning the lysosomal-cathepsin axis as an upstream proteolytic nexus coordinating apoptosis, pyroptosis, ferroptosis, and necroptosis provides a mechanistic rationale for multi-target cardioprotection and biomarker-guided therapy in myocardial ischemia-reperfusion injury.

Limitations

Direct demonstration of cathepsin-mediated execution events (such as CTSB-mediated Bid cleavage, CTSB-NLRP3 binding, and CTSB-mediated ferritin degradation) in cardiomyocytes under ischemia-reperfusion conditions remains incomplete and largely extrapolated from non-cardiac or macrophage models.
Direct measurements of endothelial lysosomal membrane permeabilization during myocardial reperfusion in vivo remain limited.
CA-074Me partially loses CTSB selectivity in intact cells by also inhibiting cathepsin L, complicating the interpretation of preclinical MIRI studies.
No cathepsin inhibitor has yet been tested in reperfused myocardial infarction patients, leaving a critical translational evidence gap between preclinical models and clinical application.
Assays for emerging multi-modal cell death biomarkers (such as GSDMD N-terminal fragment, p-MLKL, and 15-HpETE) currently lack clinical-grade precision and inter-laboratory standardization.
Temporal sequence of cathepsin-driven lysosomal membrane permeabilization across ischemic and reperfusion phases is poorly defined in cardiomyocytes and endothelial cells.
Direct cardiomyocyte evidence under ischemia-reperfusion conditions is incomplete for CTSB-mediated Bid cleavage, CTSB-NLRP3 binding, CTSB-mediated ferritin degradation, and canonical PANoptosome assembly.
CA-074Me loses strict CTSB selectivity in intact living cells by additionally inhibiting cathepsin L.
Preclinical experimental models vary widely in ischemia/reperfusion duration and species characteristics, limiting direct comparability and clinical translation.
Emerging cell death biomarkers lack analytical standardization and prospective clinical trial validation.

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Answers are grounded in this paper and cite their sources.

Implication

Offers rationale for multi-target cathepsin inhibition to overcome single-pathway failures in ischemia-reperfusion injury; leaves open clinical validation of isoform-selective approaches.

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.

Discussion

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Cite This Study

Wang et al. (2026) conducted a review in Myocardial ischemia-reperfusion injury (MIRI) in coronary artery disease. Isoform-selective cathepsin inhibitors, multi-target nanomedicine, and downstream cell death pathway modulators was evaluated. Cathepsin-driven lysosomal membrane permeabilization acts as an upstream proteolytic nexus coordinating apoptosis, pyroptosis, ferroptosis, and PANoptosis in myocardial ischemia-reperfusion injury.

synapsesocial.com/papers/6aee6b8671a75948062209d4 https://doi.org/10.3390/cells15201895

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

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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