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  3. Discovery of novel genipin derivatives as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer

Discovery of novel genipin derivatives as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2025 Oct 5:295:117823. doi: 10.1016/j.ejmech.2025.117823.
Jing-Wen Yu 1,  Yan Cao 1,  Ya-Zheng Zhu 1,  Zheng-Yu Hu 1,  Qing-Jia Ren 2,  Hui Miao 3,  Yong Yin 4,  Cao-Long Li 5
Affiliations

Affiliations

  • 1 Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 Tibetan Medicine Research Institute, Tibetan Traditional Medical College, Tibet, 850000, PR China.
  • 3 Anhui Provincial Joint Key Laboratory for Innovative Drug Research and Industry Integration, School of Chemistry and Materials Engineering, Fuyang Normal University, Fuyang, 236037, PR China.
  • 4 Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: yongyin@cpu.edu.cn.
  • 5 Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China; Tibetan Medicine Research Institute, Tibetan Traditional Medical College, Tibet, 850000, PR China. Electronic address: licl@cpu.edu.cn.
PMID: 40446585 DOI: 10.1016/j.ejmech.2025.117823
Abstract

Triple-negative breast Cancer (TNBC) is limited in treatment options due to the absence of three receptors, and evidence suggests that TNBC is sensitive to Ferroptosis. In this study, a series of genipin derivatives were synthesized through a hybridization strategy that integrated the structures of RSL3 and ML162. Among these derivatives, compound B23 demonstrated remarkable activity against the MDA-MB-231 cell line with an IC50 value of 40 nM, significantly outperforming genipin, RSL3 and ML162. Furthermore, B23 exhibited high selectivity for Ferroptosis with a selectivity ratio of up to 108-fold. Further studies revealed that B23 induces Ferroptosis by affecting the expression of ferroptosis-related proteins ACSL4, GPX4, and FTH1, thereby disrupting intracellular iron homeostasis and the GSH/GPX4 antioxidant defense system, ultimately leading to the accumulation of lipid peroxidation (LPO). Animal model demonstrated that B23 exhibited potent tumor suppression in an MDA-MB-231 xenograft model, achieving a tumor inhibition rate of 78.46 % at a dose of 4 mg/kg, without observable toxic side effects. In conclusion, B23 represents a promising Ferroptosis inducer for the treatment of TNBC and warrants further investigation.

Keywords

Ferroptosis; Ferroptosis inducer; Genipin; Triple-negative breast cancer (TNBC).

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