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The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies

Cancer Gene Therapy volume 32, pages 913–922 (2025)Cite this article

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Abstract

Glutathione peroxidase 4 (GPX4) is a key intracellular antioxidant enzyme that maintains oxidative homeostasis by catalyzing the reduction of lipid peroxides and relies on glutathione-specific inhibition of iron death. In recent years, it has been found that GPX4 exhibits significant aberrant expression in breast cancer (BC) and promotes BC development by regulating tumor cell proliferation, invasion, metastasis, and stem cell properties. More importantly, GPX4 overexpression leads to decreased sensitivity of BC to chemotherapy, radiotherapy, endocrine therapy, immune checkpoint inhibitors, and targeted therapies by inhibiting iron death, attenuating oxidative damage, and activating pro-survival signaling pathways. In this paper, we systematically review the molecular characterization of GPX4 and its cancer-promoting mechanism in BC, focusing on resolving its molecular regulatory network in multimodal therapy resistance. Based on the reversal of drug resistance and synergistic anti-tumor effects demonstrated by GPX4 inhibitors in preclinical studies, iron death induction strategies targeting GPX4 or combining with existing therapies are expected to be a new direction to overcome the bottleneck of drug resistance in BC.

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Fig. 1: Functional localization of the GPX4 gene structure and its isoforms in different cellular compartments.
Fig. 2: GPX4-regulated iron death pathway and key molecular interactions.
Fig. 3: GPX4-regulated network of iron death and tumor immune microenvironment interactions.

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Funding

The Key Research and Development Project of Zhenjiang (FZ2021057, SH2016030) Jiangsu Health International Exchange Program.

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  1. These authors contributed equally: Tingyu Gu, Kun Wang.

Authors and Affiliations

  1. Department of breast and thyroid surgery, The affiliated hospital of Jiangsu University, Zhenjiang, Jiangsu, China

    Tingyu Gu, Kun Wang, Shouchao Wang & Zhihong Zhao

  2. Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

    Xiao Yuan & Haowen Tang

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  1. Tingyu Gu
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Contributions

GTY contribution included Data curation, writing the original draft, Resources, and Validation. WK's contribution included Methodology and formal Analysis. YX、 THW, and WSC’s contributions included conceptualization and investigation. ZZH’s contribution included Project administration, Writing, review, and editing. All authors reviewed the manuscript.

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Correspondence to Zhihong Zhao.

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Gu, T., Wang, K., Yuan, X. et al. The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies. Cancer Gene Ther 32, 913–922 (2025). https://doi.org/10.1038/s41417-025-00927-3

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