PXD068417-1

PXD068417 is an original dataset announced via ProteomeXchange.

Title	A covalent fragment screen identifies ferroptosis induced by GPX4 inhibition as a vulnerability of senescent cells
Description	Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have a broad therapeutic appeal. Here, we report a senolytic screen of a library of 10,480 covalent fragments. Amongst 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as their target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress, intracellular Fe2+, and enhanced lipid oxidation, but also upregulate GPX4, which protects them from ferroptosis. Consequently, treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anti-cancer therapies with GPX4 inhibitors eliminated senescent tumour cells and improved outcomes in models of prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells, having a wide therapeutic potential.
HostingRepository	PRIDE
AnnounceDate	2026-02-24
AnnouncementXML	Submission_2026-02-23_16:11:31.689.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matthew White
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-16 08:38:58	ID requested
⏵ 1	2026-02-23 16:11:32	announced

Dataset with its publication pending

submitter keyword: GPX4, RSL3, cancer,Senescence, chloroacetamides, covalent fragments, ferroptosis, senolytics, one-two punch, covalent inhibitors

Jesus Gil
contact affiliation	Professor of Cell Proliferation Institute of Clinical Sciences - Faculty of Medicine, Imperial College London
contact email	jesus.gil@lms.mrc.ac.uk
lab head
Matthew White
contact affiliation	Department of Chemistry, Imperial College London Institute of Clinical Sciences, Imperial College London
contact email	mew21@ic.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/2026/02/PXD068417

PRIDE project URI

• PRIDE
  1. PXD068417
     1. Label: PRIDE project
     2. Name: A covalent fragment screen identifies ferroptosis induced by GPX4 inhibition as a vulnerability of senescent cells