2. Academic Validation
  3. Brusatol induced ferroptosis in osteosarcoma cells by modulating the Keap1/Nrf2/SLC7A11 signaling pathway

Brusatol induced ferroptosis in osteosarcoma cells by modulating the Keap1/Nrf2/SLC7A11 signaling pathway

  • Phytomedicine. 2025 Aug:144:156912. doi: 10.1016/j.phymed.2025.156912.
Long Zhang 1,  Doudou Luo 2,  Haijiang Ren 3,  Weijiao Fan 4,  Ziyang Yu 5,  Shibo Wang 6,  Xiang Wu 7,  Yun Xu 8,  Shun Li 9
Affiliations

Affiliations

  • 1 Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 330004, PR China; Institute for Smart Biomedical Materials, School of Materials Science & Engineering, Zhejiang Sci-Tech University, Hangzhou 310000, PR China.
  • 2 Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University, the Key Laboratory of Innate Immune Biology of Fujian Province, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, PR China.
  • 3 Department of Orthopedics, The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310003, PR China.
  • 4 Clinical Research Institute, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 330004, PR China.
  • 5 Key Laboratory for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, PR China.
  • 6 Institute for Smart Biomedical Materials, School of Materials Science & Engineering, Zhejiang Sci-Tech University, Hangzhou 310000, PR China.
  • 7 Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 330004, PR China. Electronic address: fywuxiang2@nbu.edu.cn.
  • 8 Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 330004, PR China. Electronic address: xuyun65204@163.com.
  • 9 Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 330004, PR China. Electronic address: 1148449287@qq.com.
PMID: 40494017 DOI: 10.1016/j.phymed.2025.156912
Abstract

Osteosarcoma (OS) is a rare primary malignant bone tumor. Despite ongoing research efforts, improvements in the five-year survival rate of OS patients remain limited. Therefore, there is an urgent need to identify novel therapeutic agents to improve OS prognosis. Brusatol (Bru), a quassinoid extracted from the seeds of Brucea javanica and Brucea sumatrana, has been shown to possess the potential to inhibit tumor metastasis and proliferation. In recent years, increasing evidence has highlighted the critical role of ferroptosis-a distinct form of regulated cell death-in Cancer therapy. However, whether Bru exerts its anti-OS effects by modulating Ferroptosis in OS cells remains unexplored. Our study demonstrates that Bru exhibits significant anti-OS activity. In vivo, Bru inhibited the proliferation of subcutaneous OS cells, prevented OS cell-induced tibial and fibular osteolysis, and prolonged the survival of nude mice. In vitro, Bru suppressed OS cell migration and proliferation in a dose-dependent manner. Additionally, Bru induced mitochondrial dysfunction and a marked increase in Reactive Oxygen Species in OS cells. Integrating RNA-seq analysis, our findings indicate that Bru exerts its anti-OS effects by inducing Ferroptosis through the regulation of the Keap1/Nrf2/SLC7A11 signaling pathway. Notably, the Keap1 inhibitor KI696 reversed Bru-induced Ferroptosis. Importantly, we found that the combination of Bru and the chemotherapeutic agent doxorubicin (DOX) significantly enhanced DOX's anti-OS efficacy by activating apoptotic pathways. Our study reveals that Bru, as a potent Ferroptosis inducer in OS cells, holds promise as a potential therapeutic agent for the treatment of OS.

Keywords

Brusatol; Ferroptosis; Keap1/Nrf2/SLC7A11; Osteosarcoma.

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