PXD068572

PXD068572 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 44 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. Senescent cells are primed for ferroptosis, displaying high levels of oxidative stress, intracellular Fe2+, and enhanced lipid oxidation, but also display increased levels of 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	2026-02-23
AnnouncementXML	Submission_2026-02-23_13:20:20.528.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex Montoya
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	2-pyrrolidone-5-carboxylic acid (Gln); acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-19 06:34:44	ID requested
⏵ 1	2026-02-23 13:20:21	announced

Dataset with its publication pending

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

Mr Alex Montoya
contact affiliation	MRC - Laboratory of Medical Sciences
contact email	alex.montoya@lms.mrc.ac.uk
lab head
Alex Montoya
contact affiliation	London Institute of Medical Sciences
contact email	proteomics@lms.mrc.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD068572
     1. Label: PRIDE project
     2. Name: A covalent fragment screen identifies ferroptosis induced by GPX4 inhibition as a vulnerability of senescent cells