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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
1Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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.
Insights
A novel natural compound, (20S)-protopanaxatriol ((20)S-APPT), effectively induces ferroptosis, a cell death pathway crucial for cancer treatment. This ginsenoside derivative targets FSP1, offering a safer alternative to current ferroptosis inducers.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Ferroptosis induction is a promising cancer therapy strategy.
- Existing ferroptosis inducers like GPX4 inhibitors have safety and druggability issues.
- Natural products offer a potential source for novel therapeutic agents.
Purpose of the Study:
- To identify novel ferroptosis inducers from natural products.
- To investigate the mechanism of action of identified inducers.
- To evaluate the therapeutic potential of targeting FSP1 and GCS in specific cancers.
Main Methods:
- Phenotypic screening of a 180-compound natural product library.
- In vitro and in vivo safety and efficacy assessments.
- Mechanistic studies involving FSP1 inhibition, ACSL4, mitochondrial ROS, and GCS.
Main Results:
- Identified (20S)-protopanaxatriol ((20)S-APPT), a ginsenoside derivative, as a potent ferroptosis inducer with a good safety profile.
- Demonstrated that (20)S-APPT induces ferroptosis by targeting FSP1, leading to increased lipid peroxidation and ROS.
- Showed that FSP1 inhibition alone can induce ferroptosis in some HCC and CCA cells.
- Revealed synergistic ferroptosis induction upon combined FSP1 and GCS inhibition in resistant cancer cells, sparing normal cells.
Conclusions:
- Established FSP1 as a key regulator of ferroptosis.
- (20)S-APPT is a potent ferroptosis inducer with therapeutic potential.
- Co-targeting FSP1 and GCS presents a promising strategy for treating hepatocellular carcinoma and cholangiocarcinoma.
