Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability

Mariantonietta D’Ambrosio; Matthew E.H. White; Efthymios S. Gavriil; Laura Bousset; Jodie Birch; Aleksandra Gruevska; Emiliano Pasquini; Manuel Colucci; Winnie Fong; Simone Mosole; Aurora Valdata; Dimitris Veroutis; Katie Tyson; Vikas Ranvir; Sandra Prokosch; Joaquim Pombo; Aoki Ardisson; Sanjay Khadayate; George Young; Alex Montoya; Georgia Roumelioti; Jack Houghton; Jianan Lu; Pavel V. Shliaha; Elena De Vita; Santiago Vernia; Vassilis G. Gorgoulis; Suchira Gallage; Mathias Heikenwälder; Zoe Hall; Andrea Alimonti; Iain A. McNeish; Edward W. Tate; Jesús Gil

doi:10.1038/s41556-026-01921-z

Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability

Mariantonietta D’Ambrosio
, Matthew E.H. White
, Efthymios S. Gavriil
, Laura Bousset
, Jodie Birch
, Aleksandra Gruevska
, Emiliano Pasquini
, Manuel Colucci
, Winnie Fong
, Simone Mosole
, Aurora Valdata
, Dimitris Veroutis
, Katie Tyson
, Vikas Ranvir
, Sandra Prokosch
, Joaquim Pombo
, Aoki Ardisson
, Sanjay Khadayate
, George Young
, Alex Montoya

Georgia Roumelioti, Jack Houghton, Jianan Lu, Pavel V. Shliaha, Elena De Vita, Santiago Vernia, Vassilis G. Gorgoulis, Suchira Gallage, Mathias Heikenwälder, Zoe Hall, Andrea Alimonti, Iain A. McNeish, Edward W. Tate, Jesús Gil (Lead / Corresponding author)

Cancer Research

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Abstract

Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 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 a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe²⁺, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.

Original language	English
Pages (from-to)	915-929
Journal	Nature Cell Biology
Volume	28
Early online date	24 Apr 2026
DOIs	https://doi.org/10.1038/s41556-026-01921-z
Publication status	Published - May 2026

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cell Biology

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D’Ambrosio, M., White, M. E. H., Gavriil, E. S., Bousset, L., Birch, J., Gruevska, A., Pasquini, E., Colucci, M., Fong, W., Mosole, S., Valdata, A., Veroutis, D., Tyson, K., Ranvir, V., Prokosch, S., Pombo, J., Ardisson, A., Khadayate, S., Young, G., ... Gil, J. (2026). Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability. Nature Cell Biology, 28, 915-929. https://doi.org/10.1038/s41556-026-01921-z

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title = "Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability",

abstract = "Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 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 a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.",

author = "Mariantonietta D{\textquoteright}Ambrosio and White, \{Matthew E.H.\} and Gavriil, \{Efthymios S.\} and Laura Bousset and Jodie Birch and Aleksandra Gruevska and Emiliano Pasquini and Manuel Colucci and Winnie Fong and Simone Mosole and Aurora Valdata and Dimitris Veroutis and Katie Tyson and Vikas Ranvir and Sandra Prokosch and Joaquim Pombo and Aoki Ardisson and Sanjay Khadayate and George Young and Alex Montoya and Georgia Roumelioti and Jack Houghton and Jianan Lu and Shliaha, \{Pavel V.\} and \{De Vita\}, Elena and Santiago Vernia and Gorgoulis, \{Vassilis G.\} and Suchira Gallage and Mathias Heikenw{\"a}lder and Zoe Hall and Andrea Alimonti and McNeish, \{Iain A.\} and Tate, \{Edward W.\} and Jes{\'u}s Gil",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = may,

doi = "10.1038/s41556-026-01921-z",

language = "English",

volume = "28",

pages = "915--929",

journal = "Nature Cell Biology",

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D’Ambrosio, M, White, MEH, Gavriil, ES, Bousset, L, Birch, J, Gruevska, A, Pasquini, E, Colucci, M, Fong, W, Mosole, S, Valdata, A, Veroutis, D, Tyson, K, Ranvir, V, Prokosch, S, Pombo, J, Ardisson, A, Khadayate, S, Young, G, Montoya, A, Roumelioti, G, Houghton, J, Lu, J, Shliaha, PV, De Vita, E, Vernia, S, Gorgoulis, VG, Gallage, S, Heikenwälder, M, Hall, Z, Alimonti, A, McNeish, IA, Tate, EW & Gil, J 2026, 'Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability', Nature Cell Biology, vol. 28, pp. 915-929. https://doi.org/10.1038/s41556-026-01921-z

TY - JOUR

T1 - Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability

AU - D’Ambrosio, Mariantonietta

AU - White, Matthew E.H.

AU - Gavriil, Efthymios S.

AU - Bousset, Laura

AU - Birch, Jodie

AU - Gruevska, Aleksandra

AU - Pasquini, Emiliano

AU - Colucci, Manuel

AU - Fong, Winnie

AU - Mosole, Simone

AU - Valdata, Aurora

AU - Veroutis, Dimitris

AU - Tyson, Katie

AU - Ranvir, Vikas

AU - Prokosch, Sandra

AU - Pombo, Joaquim

AU - Ardisson, Aoki

AU - Khadayate, Sanjay

AU - Young, George

AU - Montoya, Alex

AU - Roumelioti, Georgia

AU - Houghton, Jack

AU - Lu, Jianan

AU - Shliaha, Pavel V.

AU - De Vita, Elena

AU - Vernia, Santiago

AU - Gorgoulis, Vassilis G.

AU - Gallage, Suchira

AU - Heikenwälder, Mathias

AU - Hall, Zoe

AU - Alimonti, Andrea

AU - McNeish, Iain A.

AU - Tate, Edward W.

AU - Gil, Jesús

PY - 2026/5

Y1 - 2026/5

N2 - Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 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 a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.

AB - Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 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 a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.

UR - https://www.scopus.com/pages/publications/105037383769

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DO - 10.1038/s41556-026-01921-z

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AN - SCOPUS:105037383769

SN - 1465-7392

VL - 28

SP - 915

EP - 929

JO - Nature Cell Biology

JF - Nature Cell Biology

ER -

Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability

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