Article

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

Fan-yu Liu1,2, Yuan-jie Yang1,2, Xue-long Wang3, Yan Hong1, Xiao-peng Ou-Yang1,4, Lu Chang5, Nan-lin Zhu5, Ao Huang6, Min-min Zhang1, Jia Liu5,7, Mei-yu Geng1,2,8, Ai-jun Shen1,3
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 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310058, China
8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
Correspondence to: Jia Liu: jia.liu@simm.ac.cn, Mei-yu Geng: mygeng@simm.ac.cn, Ai-jun Shen: shenaj@lglab.ac.cn,
DOI: 10.1038/s41401-025-01589-5
Received: 19 May 2025
Accepted: 19 May 2025
Advance online: 23 June 2025

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.
Keywords: Ginsenoside

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