Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling PMID: 41526742

ADC Targets in Oncology

2026-04-10

Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling

Nat Aging. 2026 Feb;6(2):349-367. doi: 10.1038/s43587-025-01030-w.

Javier Moral-Sanz ^# ¹ ² , Isabel Fernández-Carrasco ^# ³ , Valentina Ramponi ⁴ , Amanda Garrido ⁵ , Izhar Karbat ⁶ , Pablo Cabezas-Sainz ⁷ , Esperanza Rivera-de-Torre ⁸ ⁹ , Osama Elsallabi ¹⁰ ¹¹ , Roberto Martín-Hernández ¹² , José L López-Aceituno ³ , Nathan L Price ⁵ , Laura Sanchez ⁷ , Gonzalo Colmenarejo ¹² , Álvaro Martínez-Del-Pozo ⁸ , Irina Vetter ¹³ ¹⁴ , Angel Cogolludo ¹⁵ ¹⁶ , Francisco Perez-Vizcaino ¹⁵ ¹⁶ , Jorge Del-Pozo ¹⁷ , Eitan Reuveny ⁶ , Manuel A Fernández-Rojo ¹⁸ ¹⁹ , Paul D Robbins ¹⁰ , Rafael de Cabo ⁵ ²⁰ , Manuel Serrano ⁴ ²¹ , Maria P Ikonomopoulou ²² ²³

Affiliations

1. Translational Venomics Group, Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain. [email protected].
2. Syneos Health, Madrid, Spain. [email protected].
3. Translational Venomics Group, Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain.
4. Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
5. Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
6. Departments of Biomolecular Sciences and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
7. Department of Zoology, Genetics and Physical Anthropology, Universidad de Santiago de Compostela, Lugo, Spain.
8. Department of Biochemistry and Molecular Biology, Faculty of Chemistry, Complutense University, Madrid, Spain.
9. Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.
10. Masonic Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
11. Department of Medicine and Science of Aging, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy.
12. Cheminformatics & Artificial Intelligence Group, Madrid Institute for Advances Studies in Nutrition (IMDEA Nutrition), Madrid, Spain.
13. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.
14. School of Pharmacy and Pharmaceutical Sciences, The University of Queensland, Woolloongabba, Queensland, Australia.
15. Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain.
16. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
17. R(D)SVS, University of Edinburgh, Easter Bush Campus, Roslin, Edinburgh, UK.
18. Hepatic Regenerative Medicine Group, Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain.
19. Frazer Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
20. Nutritional Interventions Group. Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain.
21. Altos Labs, Cambridge Institute of Science, Granta Park, UK.
22. Translational Venomics Group, Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain. [email protected].
23. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. [email protected].
# Contributed equally.

Abstract

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.