PXD054440-1

PXD054440 is an original dataset announced via ProteomeXchange.

Title	The proteomic landscape of proteotoxic stress in a fibrogenic liver disease
Description	Protein misfolding diseases, including alpha-1 antitrypsin deficiency (AATD), pose significant health challenges, yet their progression at the cellular level remains poorly understood. Here, we employ spatial proteomics by mass spectrometry and machine learning to map the molecular landscape of AATD in human liver tissue at high resolution. Our approach, combining Deep Visual Proteomics with single-cell analysis in a patient cohort, characterized early and late responses to protein aggregation across fibrosis stages. We achieved a remarkable quantitative depth of 2,800 proteins per single hepatocyte shape, providing detailed insights into cellular heterogeneity. This comprehensive biological dataset revealed an unexpected early integrated peroxisomal upregulation, preceding the canonical unfolded protein response. Our single-cell data demonstrate that alpha-1 antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between neighboring hepatocytes. By integrating proteomic data with AI-guided image analysis across multiple disease stages, we identify a terminal hepatocyte phenotype, marked by globular protein aggregates and distinct proteomic signatures including elevated TNFSF10/TRAIL expression. This phenotype may represent a critical stage in disease progression. Our study unveils novel insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders and beyond, setting a new standard for understanding disease progression at the single-cell level in human tissue.
HostingRepository	PRIDE
AnnounceDate	2025-02-20
AnnouncementXML	Submission_2025-02-20_10:31:42.052.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-31 06:09:07	ID requested
⏵ 1	2025-02-20 10:31:42	announced

Dataset with its publication pending

submitter keyword: alpha-1 antitrypsin deficiency,proteotoxic stress, single cell, deep visual proteomics, liver

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Germany
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
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/2025/02/PXD054440

PRIDE project URI

• PRIDE
  1. PXD054440
     1. Label: PRIDE project
     2. Name: The proteomic landscape of proteotoxic stress in a fibrogenic liver disease