PXD048231-1

PXD048231 is an original dataset announced via ProteomeXchange.

Title	Cytotoxicity and Toxicoproteomic Analysis of Pioglitazone Exposure in Human-derived Cardiomyocytes
Description	Pioglitazone (PGZ) is a peroxisome proliferator-activated receptor gamma agonist widely used as an insulin sensitiser agent for type II diabetes mellitus. The heterogeneity of PGZ effects on cardiac tissue has remained controversial, as contradictory data exist in the literature. Nevertheless, a consensus has reported an associated increased risk of heart failure (HF) following chronic systemic exposure to PGZ, which has hampered its clinical use in diabetes management. The mechanism of PGZ-induced HF remains largely uncharacterised. Here, we report a comprehensive in vitro study combining a novel toxico-proteomic pipeline with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into PGZ cardiotoxicity and identify driver proteins associated with such effects. Cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production following PGZ exposure, suggesting that this decline underpins PGZ cardiotoxicity. Interestingly, proteomics analysis revealed that the mitochondrial dysfunction was attributed to PGZ mediating mitochondrial uncoupling and ultimately cardiomyocyte death. The type of cell death was also found to be related to the mitochondria—protein upregulation in the phosphoglycerate mutase family 5–dynamin-related protein 1 axis, suggesting mitochondrial-mediated necroptosis. Furthermore, our analysis suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through integrin-signalling pathways, responsible for PGZ-induced myocardial contractile failure. Collectively, our findings provide substantial mechanistic insight into PGZ adverse effects and may eventually provide the rationale for future optimisation of antidiabetic therapies.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_12:39:14.578.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Abdullah AlSultan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-03 17:35:43	ID requested
⏵ 1	2025-05-06 12:39:15	announced

10.1007/s11306-024-02201-3;

Al Sultan A, Rattray Z, Rattray NJW, Integrative analysis of toxicometabolomics and toxicoproteomics data: new molecular insights into thiazolidinedione-induced cardiotoxicity. Metabolomics, 21(1):1(2024) [pubmed]

submitter keyword: Pioglitazone

mitochondrial dysfunction

WGCNA

label-free protein quantification

Nicholas J. Rattray
contact affiliation	Strathclyde Institute of Pharmacy and Biomedical Sciences
contact email	nicholas.rattray@strath.ac.uk
lab head
Abdullah AlSultan
contact affiliation	University of Strathclyde
contact email	abdullah.alsultan@strath.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD048231

PRIDE project URI

• PRIDE
  1. PXD048231
     1. Label: PRIDE project
     2. Name: Cytotoxicity and Toxicoproteomic Analysis of Pioglitazone Exposure in Human-derived Cardiomyocytes