Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Zoledronic Acid Inhibits the Growth of ER-Positive Breast Cancer Cells by Inducing Ferroptosis

  • Shaofei Yuan (Department of Medical Oncology, Rui'an People's Hospital, The Third Affiliated Hospital of Wenzhou Medical University) ;
  • Dejin Shi (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Yiyin Xu (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Tao Wu (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Shuifeng Liang (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Dinghao Chen (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Jiayi Wang (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Guang Wu (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University) ;
  • Jiawei Cao (Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University)
  • Received : 2025.07.09
  • Accepted : 2026.02.12
  • Published : 2026.05.01
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Abstract

Zoledronic acid (ZA), a nitrogen-containing bisphosphonate with established clinical utility in osteoporosis management, exhibits emerging antitumor potential in estrogen receptor-positive breast cancer. However, the molecular mechanisms underlying its non-apoptotic anticancer effects remain poorly characterized. This study revealed that ZA induced ferroptosis in ER+ breast cancer cells through dual suppression of cystine-glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4), key repressors of ferroptosis. Pharmacological inhibition of ferroptosis using Ferrostatin-1 significantly attenuated ZA-induced cytotoxicity, while combinatorial treatment with the GPX4 inhibitor RSL3 synergistically enhanced lipid peroxidation and cell death. Mechanistically, ZA activated the Hippo-YAP signaling pathway, promoting YAP phosphorylation, proteasomal degradation, and cytoplasmic retention, thereby silencing SLC7A11 and GPX4. We established a novel metabolic vulnerability in hormone-responsive malignancies. These findings position ZA as a bifunctional ferroptosis inducer in ER+ breast cancer, offering a promising strategy to overcome endocrine resistance.

Keywords

Acknowledgement

This study was supported by Natural Science Foundation of Zhejiang Province, China (LQ23H160012), The Medical and Health Research Project of Zhejiang Province (2025KY1523), Wenzhou Science and Technology Bureau of China (Y20240037, Y20240132), Beijing Science And Technology Innovation Medical Development Foundation (KC2023-JX-0186-PQ011), Wenzhou Medical University Startup funds, Xinmiao Talent Program of Zhejiang Province (2024R413A005), and in part supported by the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A).

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