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GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer

Marie Sabatier1, Mayher Kaur1, Milena Chaufan1

  • 1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 18, 2026
PubMed

Insights

Generating resistance to ferroptosis inhibitors like RSL3 and ML210 alters cancer cell metabolism and epithelial characteristics, impacting metastasis differently depending on the route of spread.

Area of Science:

  • Oncology
  • Cancer Biology
  • Metastasis Research

Background:

  • Ferroptosis induction is a promising cancer therapy strategy using small-molecule modulators.
  • Glutathione peroxidase 4 (GPX4) inhibitors (e.g., RSL3, ML210) induce ferroptosis by neutralizing lipid peroxides.
  • Limited knowledge exists on GPX4-inhibitor resistance's role in cancer metastasis.

Purpose of the Study:

  • To investigate the metastatic potential of cancer cells adapted to GPX4 inhibition.
  • To characterize metabolic and phenotypic changes in GPX4-inhibitor-resistant (GPX4i) cancer cells.

Main Methods:

  • Triple-negative breast cancer cell lines (M231, 4T1) were cultured with GPX4 inhibitors to generate resistant cell lines (GPX4i).
  • Metabolic and lipidomic profiles of tumors derived from GPX4i-resistant cells and parental cells were analyzed.
  • Changes in epithelial-like markers (vimentin, EpCAM) were assessed.
  • Spontaneous and intravenous metastasis models were used to evaluate metastatic burden.

Main Results:

  • GPX4i-resistant tumors exhibited distinct metabolic and lipidomic profiles compared to parental tumors.
  • Resistance to GPX4 inhibitors induced a shift towards an epithelial-like state (decreased vimentin, increased EpCAM).
  • GPX4i-resistant cells formed fewer spontaneous metastases from primary tumors.
  • No significant difference in overall metastatic burden was observed upon intravenous injection.

Conclusions:

  • Long-term in vitro exposure to GPX4 inhibitors induces significant alterations in cancer cell phenotypes.
  • GPX4 inhibitor resistance influences the metastatic behavior of cancer cells, particularly spontaneous metastasis.
  • These findings highlight the complex interplay between ferroptosis resistance and cancer dissemination.
Keywords:
ferroptosislipid peroxidationmetastasestumor microenvironment

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