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Updated: Jan 14, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

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

Javier Moral-Sanz1,2, Isabel Fernández-Carrasco3, Valentina Ramponi4

  • 1Translational Venomics Group, Madrid Institute for Advanced Studies in Nutrition (IMDEA Nutrition), Madrid, Spain. javier.moralsanz@syneoshealth.com.

Nature Aging
|January 12, 2026
PubMed

Insights

Sticholysin I (StnI) and its variant StnIG are novel senotoxins that selectively kill senescent cancer cells. This discovery offers a new strategy to enhance chemotherapy effectiveness and treat solid tumors.

Area of Science:

  • Cellular senescence
  • Cancer biology
  • Pharmacology

Background:

  • Cellular senescence drives aging and hinders tumor progression but can promote inflammation and relapse.
  • Persistent senescent cells in the tumor microenvironment can compromise chemotherapy efficacy.

Purpose of the Study:

  • To identify and characterize senolytic agents targeting chemotherapy-induced senescent cells.
  • To explore the therapeutic potential of sticholysin I (StnI) and its engineered variant (StnIG) in cancer therapy.

Main Methods:

  • Investigated the senolytic properties of StnI and StnIG on senescent cancer and primary cells.
  • Analyzed the mechanism of action, including membrane binding and ion flux.
  • Evaluated the in vivo efficacy of StnIG in combination with chemotherapy in mouse models of solid tumors.

Main Results:

  • StnI and StnIG selectively reduced the viability of senescent cells.
  • Selectivity is mediated by binding to specific lipids and compromised membrane asymmetry in senescent cells.
  • StnIG induced ion influxes (Na+, Ca2+) and efflux (K+), leading to apoptosis and pyroptosis.
  • StnIG synergized with chemotherapy to achieve tumor remission in mice.

Conclusions:

  • StnI and StnIG function as senotoxins, selectively eliminating senescent cells.
  • These senotoxins have potential as a novel therapeutic strategy to enhance cancer chemotherapy.
  • StnIG demonstrates translational potential for improving solid tumor treatment outcomes.

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