Zoledronic Acid Inhibits the Growth of ER-Positive Breast Cancer Cells by Inducing Ferroptosis
10.4062/biomolther.2025.132
- Author:
Shaofei YUAN
1
;
Dejin SHI
;
Yiyin XU
;
Tao WU
;
Shuifeng LIANG
;
Dinghao CHEN
;
Jiayi WANG
;
Guang WU
;
Jiawei CAO
Author Information
1. Department of Medical Oncology, Rui’an People’s Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2026;34(3):608-617
- CountryRepublic of Korea
- Language:English
-
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 nonapoptotic 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.
