Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling
Senescence is a driver of aging and a barrier to tumor progression, but its persistent accumulation drives inflammation and relapse. Thus, the success of chemotherapy could be jeopardized when senescence emerges in the tumor microenvironment. Here we identified the senolytic properties of a pore-forming toxin, sticholysin I (StnI). StnI and our engineered improved form, StnIG, selectively hampers viability of chemotherapy-induced senescent cancer cells, as well as senescent primary cells. We show that its selectivity is mediated by specific binding and lipid ratios associated with senescence, including compromised membrane bilayer asymmetry. Mechanistically, StnIG triggers sodium and calcium influx and an enduring potassium efflux in senescent cells. Calcium triggers the opening of calcium-activated potassium channels, leading to cell death by apoptosis and pyroptosis. Finally we show that StnIG synergizes with senescence-inducing chemotherapy to drive remission of solid tumors in mice. Our findings define StnI and StnIG as senotoxins with translational potential for cancer therapy.
Authors
- Irina Vetter (ORCID: https://orcid.org/0000-0002-3594-9588)
- Osama Elsallabi (ORCID: https://orcid.org/0000-0002-8467-5480)
- Manuel A. Fernández‐Rojo (ORCID: https://orcid.org/0000-0002-2240-1951)
- Gonzalo Colmenarejo (ORCID: https://orcid.org/0000-0002-8249-4547)
- Eitan Reuveny (ORCID: https://orcid.org/0000-0003-4945-9683)
- I. Karbat
- Laura García Sánchez (ORCID: https://orcid.org/0000-0001-6095-1148)
- Pérez-Vizcaíno Francisco
- Javier Moral‐Sanz (ORCID: https://orcid.org/0000-0001-8602-8554)
- Amanda Garrido (ORCID: https://orcid.org/0000-0003-3140-3251)
- Valentina Ramponi (ORCID: https://orcid.org/0000-0002-1947-2273)
- M. Serrano
- Nathan L. Price
- Álvaro Martínez-del-Pozo
- Rafael de Cabo
- Paul D. Robbins
- Jorge Del-Pozo
- Angel Cogolludo
- Roberto Martín-Hernández
- Isabel Fernández-Carrasco
- Pablo Cabezas-Sainz
- Esperanza Rivera-de-Torre
- José L. López-Aceituno
Institutions
- Madrid Institute for Advanced Studies (ES)
- Universidad Complutense de Madrid (ES)
- University of Minnesota (US)
- Translational Research Institute (AU)
- Roslin Institute (GB)
- The University of Queensland (AU)
- Universidade de Santiago de Compostela (ES)
- Instituto de Salud Carlos III (ES)
- University of Chieti-Pescara (IT)
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES)
- Syneos Health (United States) (US)
- Granta Design (United Kingdom) (GB)
- Institute for Research in Biomedicine (ES)
- Roslin Cells (United Kingdom) (GB)
- National Institute on Aging (US)
- Syneos Health (India) (IN)
- Weizmann Institute of Science (IL)
- Technical University of Denmark (DK)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Aging
- Published
- 2026-01-12
- DOI
- https://doi.org/10.1038/s43587-025-01030-w
- Citations
- 1
- Primary Topic
- Marine Invertebrate Physiology and Ecology
- Type
- article
- Field-Weighted Citation Impact
- 43.71
Funders
- European Commission
- Xunta de Galicia
- National Institutes of Health
- European Regional Development Fund
- Agencia Estatal de Investigación