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Updated: Dec 20, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death
Yang Liu1, Yuan Wang1, Jiao Liu1
1The Third Affiliated Hospital, Guangzhou Medical University, 510510, Guangzhou, Guangdong, China.
Abstract:
Ferroptosis has become a topic of rapidly growing interest in recent years, and has possible therapy implications in cancer therapy. Although excessive autophagy may contribute to ferroptosis, its underlying molecular mechanism remains largely unknown. Here, we provide novel evidence that the interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells. Moreover, GPX4 plays an essential role in the inhibition of autophagy-dependent ferroptosis induced by rapamycin and RSL3. Consequently, GPX4 depletion by RNAi enhances the anticancer activity of rapamycin and RSL3 in vitro or in vivo. These findings not only increase our understanding of stress responses in cell death, but may also raise the possibility of developing new antitumor therapy targeting autophagy-dependent cell death.
Insights
Mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) signals regulate autophagy-dependent ferroptosis in pancreatic cancer. GPX4 depletion enhances anticancer drug efficacy, suggesting new therapeutic strategies.
Area of Science:
- Cell biology
- Molecular oncology
- Cancer therapy
Background:
- Ferroptosis is a key cell death pathway with potential in cancer treatment.
- The molecular mechanisms linking autophagy and ferroptosis are not fully understood.
Purpose of the Study:
- To investigate the role of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) in autophagy-dependent ferroptosis.
- To explore the therapeutic potential of targeting this pathway in human pancreatic cancer.
Main Methods:
- Utilized rapamycin (autophagy inducer) and RSL3 (ferroptosis activator) in human pancreatic cancer cells.
- Investigated the effects of these agents on MTOR activation and GPX4 protein levels.
- Employed RNA interference (RNAi) to deplete GPX4.
- Assessed the impact of GPX4 depletion on drug efficacy in vitro and in vivo.
Main Results:
- Both rapamycin and RSL3 inhibited MTOR activation and induced GPX4 degradation.
- GPX4 was essential in suppressing autophagy-dependent ferroptosis induced by rapamycin and RSL3.
- GPX4 depletion significantly enhanced the anticancer effects of rapamycin and RSL3.
Conclusions:
- The interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptosis in pancreatic cancer.
- Targeting GPX4 could enhance the efficacy of existing anticancer therapies.
- These findings offer novel therapeutic strategies for autophagy-dependent cell death in cancer treatment.
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