Dataset Information

A covalent fragment screen identifies ferroptosis induced by GPX4 inhibition as a vulnerability of senescent cells

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Alex Montoya

LAB HEAD: Mr Alex Montoya

PROVIDER: PXD068572 | Pride | 2026-02-23

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20250303_164841_b008p003e004.sne	Other
	Hsapiens_UP000005640_9606_20250113.fasta	Fasta
	b008_p003_e004_159D_2h_1.raw	Raw
	b008_p003_e004_159D_2h_2.raw	Raw
	b008_p003_e004_159D_2h_3.raw	Raw

Items per page:

1 - 5 of 109

Similar Datasets

Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.

Dataset Information

A covalent fragment screen identifies ferroptosis induced by GPX4 inhibition as a vulnerability of senescent cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets