Ginsenoside (20)S-APPT induces ferroptosis in hepatocellular carcinoma and cholangiocarcinoma by targeting FSP1

  • Acta Pharmacol Sin. 2025 Jun 23. doi: 10.1038/s41401-025-01589-5.
Fan-Yu Liu  #  1  2 ,  Yuan-Jie Yang  #  1  2 ,  Xue-Long Wang  3 ,  Yan Hong  1 ,  Xiao-Peng Ou-Yang  1  4 ,  Lu Chang  5 ,  Nan-Lin Zhu  5 ,  Ao Huang  6 ,  Min-Min Zhang  1 ,  Jia Liu  7  8 ,  Mei-Yu Geng  9  10  11 ,  Ai-Jun Shen  12  13
Affiliations
  • 1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. Lingang Laboratory, Shanghai, 200031, China.
  • 4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5. "Belt and Road" Joint Laboratory for Natural Products and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China.
  • 7. "Belt and Road" Joint Laboratory for Natural Products and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310058, China. [email protected].
  • 9. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 10. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 11. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. [email protected].
  • 12. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 13. Lingang Laboratory, Shanghai, 200031, China. [email protected].
  • # Contributed equally.
PMID: 40550962 DOI: 10.1038/s41401-025-01589-5
Abstract

Triggering Ferroptosis has recently been recognized as a promising approach for Cancer treatment. However, current Ferroptosis inducers, such as Glutathione Peroxidase 4 (GPX4) inhibitors, face limitations in terms of druggability and safety. In this study, we performed a phenotypic screen of a 180-compound natural product library and identified (20S)-protopanaxatriol ((20)S-APPT), a ginsenoside derivative, as a potent Ferroptosis inducer with a favorable safety profile both in vitro and in vivo. We demonstrated that (20)S-APPT induced Ferroptosis by targeting the plasma membrane-localized CoQ10 oxidoreductase FSP1. FSP1 inhibition promoted ACSL4-dependent arachidonic acid oxidation and mitochondrial ROS production, thereby increasing Ferroptosis. Intriguingly, we revealed that FSP1 inhibition alone was sufficient to trigger Ferroptosis in a subset of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) cells. Furthermore, the combined inhibition of FSP1 and γ-glutamylcysteine synthetase (GCS) synergistically induced Ferroptosis in otherwise resistant Cancer cells while sparing noncancerous cells. These results establish a previously unrecognized role for FSP1 in driving Ferroptosis and highlight the therapeutic potential of cotargeting FSP1 and GCS in HCC and CCA.

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