PXD077417-1

PXD077417 is an original dataset announced via ProteomeXchange.

Title	Cathepsin L-Dependent Lysosomal Cardiomyocyte Death via Pyroptotic Macrophage-Derived sEV PLA2G4A Transfer: A Novel Mechanism and Potential Therapeutic Target in Fulminant Myocarditis
Description	Background: Fulminant myocarditis (FM) is an increasingly recognized cause of acute, rapidly progressive inflammatory cardiomyopathy, with limited treatment options and a high risk of cardiogenic shock and death. Despite its growing clinical impact, the mechanisms by which immune cells induce cardiomyocyte death remain poorly defined. Methods: We analyzed cardiac biopsies and plasma from patients with FM and established coxsackievirus B3 (CVB3)-induced FM in mice, including bone marrow–specific GSDMD knockout and myeloid cell-specific Pla2g4a-deficient strains. Cardiac function was assessed by echocardiography and catheterization. Single-nucleus RNA sequencing, cell-based assays, and extracellular vesicle (EV) studies were used to interrogate programmed cell death pathways and lysosomal injury. Results: Transcriptomic and histological analyses revealed a prominent increase in lysosome-dependent cell death (LDCD) in cardiomyocytes during FM, accompanied by lysosomal swelling and upregulation of cathepsin in both patients and mice. Inhibition or knockdown of cathepsin L (CTSL) markedly reduced cardiomyocyte death and improved cardiac function, whereas blockade of cathepsin B or D was ineffective. Cardiomyocytes exposed directly to CVB3 failed to undergo lysosomal membrane permeabilization (LMP), but conditioned medium or EVs from pyroptotic macrophages induced LMP, CTSL activation, and cell death. Bone marrow–specific GSDMD knockout attenuated macrophage pyroptosis and cardiomyocyte LDCD, and improved cardiac function in CVB3-infected mice. Proteomic profiling identified PLA2G4A as a critical pyroptotic EV cargo. Pyroptotic EVs delivered PLA2G4A to cardiomyocyte lysosomes, triggering membrane damage and LDCD. Myeloid cell-specific Pla2g4a deletion reduced lysosomal injury, CTSL activation, and mortality in CVB3-infected mice. Pharmacologic inhibition with the FDA-approved drug amantadine suppressed CTSL activity and preserved cardiac function in FM. Conclusions: FM progression is driven, at least in part, by macrophage pyroptosis, which releases EVs that deliver PLA2G4A to cardiomyocytes and trigger CTSL-dependent lysosomal cell death. This newly defined macrophage sEV-PLA2G4A-CTSL axis establishes a central mechanism of immune-mediated cardiomyocyte loss in FM and identifies lysosomal CTSL/PLA2G4A inhibition, including drug repurposing strategies such as amantadine, as a promising mechanistically targeted therapy.
HostingRepository	iProX
AnnounceDate	2026-04-21
AnnouncementXML	Submission_2026-04-20_20:14:18.157.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wenjun Yan
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-20 20:14:03	ID requested
⏵ 1	2026-04-20 20:14:18	announced

Dataset with its publication pending

submitter keyword: fulminant myocarditis, extracellular vesicle, lysosome-dependent cell death, macrophage pyroptosis, PLA2G4A

Wenjun Yan
contact affiliation	Fourth Military Medical University
contact email	wenjunyan@fmmu.edu.cn
lab head
Wenjun Yan
contact affiliation	Fourth Military Medical University
contact email	wenjunyan@fmmu.edu.cn
dataset submitter

iProX dataset URI