PXD044477

PXD044477 is an original dataset announced via ProteomeXchange.

Title	Single cell spatial proteomics identifies JAK/STAT pathway as actionable therapeutic target in toxic epidermal necrolysis
Description	Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse drug reaction and an emerging public health issue 1-3. Triggered by common medications, patients suffer from fulminant epidermal detachment and long-term sequalae. Although molecular mechanisms driving keratinocyte cytotoxicity have been reported, no effective therapy exists4-6. In recent years, powerful omics technologies have expanded into spatial context and we reasoned that single cell spatial proteomics could uncover novel therapeutic targets in TEN. Applying Deep Visual Proteomics7,8 to formalin fixed paraffin embedded archived skin-tissue biopsies of three types of cutaneous drug reactions with varying severity quantified over 5,000 proteins in keratinocytes and skin-infiltrating immune cells. Most strikingly, this revealed a robust enrichment of Type-I- and -II interferon signature in the immune cell and keratinocyte compartment of TEN patients, along with a drastic activation of pSTAT1. Targeted inhibition with pan-JAK inhibitor (JAKi) Tofacitinib reduced keratinocyte-directed cytotoxicity in a novel live-cell imaging assay, using patient-derived keratinocytes and PBMCs. Furthermore, oral administration of pan-JAKi Tofacitinib or Baricitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. This study uncovers the JAK-STAT and interferon signaling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAK inhibition as a curative therapy.
HostingRepository	PRIDE
AnnounceDate	2025-01-13
AnnouncementXML	Submission_2025-01-13_12:42:09.235.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	monohydroxylated residue
Instrument	Bruker Daltonics timsTOF series

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-10 03:08:27	ID requested
⏵ 1	2025-01-13 12:42:10	announced

10.1038/s41586-024-08061-0;

Nordmann TM, Anderton H, Hasegawa A, Schweizer L, Zhang P, Stadler PC, Sinha A, Metousis A, Rosenberger FA, Zwiebel M, Satoh TK, Anzengruber F, Strauss MT, Tanzer MC, Saito Y, Gong T, Thielert M, Kimura H, Silke N, Rodriguez EH, Restivo G, Nguyen HH, Gross A, Feldmeyer L, Joerg L, Levesque MP, Murray PJ, Ingen-Housz-Oro S, Mund A, Abe R, Silke J, Ji C, French LE, Mann M, Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature, 635(8040):1001-1009(2024) [pubmed]

submitter keyword: skin, spatial proteomics, adverse drug reaction,DVP

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction; Max-Planck Institute of Biochemistry; Martinsried, Bavaria, 82152; 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/2025/01/PXD044477

PRIDE project URI

• PRIDE
  1. PXD044477
     1. Label: PRIDE project
     2. Name: Single cell spatial proteomics identifies JAK/STAT pathway as actionable therapeutic target in toxic epidermal necrolysis