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SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity
Xian Liu1, Cheng Chen2, Dong Han2
1Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 100850 Beijing, China.
Abstract:
Triptolide exhibits promising efficacy in various cancers and immune diseases while its clinical application has been strongly restricted by its severe side effects, especially cardiotoxicity. However, the underlying mechanism of triptolide-induced cardiotoxicity (TIC) remains unclear. The RNA-seq analysis of triptolide-injured AC16 human cardiomyocyte cell line hinted that ferroptosis is involved in TIC. Further experimental validations proved that triptolide triggered ferroptosis, as evidenced by significant accumulation of lipid peroxidation (4-HNE and MDA levels) and ferrous iron, as well as depletion of intracellular GSH. Furthermore, triptolide-induced iron overload involved the upregulation of TF/TRFC/DMT1 signal axis and the degradation of ferritin, which contribute to ROS generation via Fenton reaction. In addition, inhibition of the antioxidant Nrf2/HO-1 pathway was observed in TIC, which may also lead to the overproduction of lethal lipid peroxides. Mechanistically, using streptavidin-biotin affinity pull-down assay and computational molecular docking, we unveiled that triptolide directly binds to SLC7A11 to inactivate SLC7A11/GPX4 signal axis. More importantly, employment of a ferroptosis inhibitor Ferrostatin-1 alleviated TIC by partially reversing the inhibitory effects of triptolide on SLC7A11/GPX4 signal. Altogether, our study demonstrated that SLC7A11/GPX4 inactivation-mediated ferroptosis contributed to the pathogenesis of TIC. Combating ferroptosis may be a promising therapeutic avenue to prevent TIC.
Insights
Triptolide causes heart damage by triggering ferroptosis, a cell death pathway involving iron and lipid peroxidation. Targeting this pathway may prevent triptolide-induced cardiotoxicity.
Area of Science:
- Cardiovascular Research
- Toxicology
- Cell Death Mechanisms
Background:
- Triptolide shows therapeutic potential but causes severe cardiotoxicity, limiting its use.
- The mechanism behind triptolide-induced cardiotoxicity (TIC) is not fully understood.
- Initial RNA-seq analysis suggested ferroptosis involvement in TIC.
Purpose of the Study:
- To elucidate the mechanism of triptolide-induced cardiotoxicity (TIC).
- To investigate the role of ferroptosis in TIC.
- To identify potential therapeutic strategies against TIC.
Main Methods:
- RNA-sequencing on triptolide-injured human cardiomyocytes (AC16 cells).
- Biochemical assays to measure lipid peroxidation, iron levels, and glutathione.
- Analysis of iron regulatory pathways (TF/TRFC/DMT1, ferritin).
- Investigation of the Nrf2/HO-1 antioxidant pathway.
- Streptavidin-biotin pull-down assay and molecular docking to identify triptolide's direct target.
- Treatment with ferroptosis inhibitor Ferrostatin-1.
Main Results:
- Triptolide induced ferroptosis, characterized by increased lipid peroxidation and iron, and decreased glutathione.
- Triptolide upregulated iron import (TF/TRFC/DMT1) and degraded ferritin, leading to iron overload and ROS generation.
- The Nrf2/HO-1 antioxidant pathway was inhibited, contributing to oxidative stress.
- Triptolide directly binds to SLC7A11, inactivating the SLC7A11/GPX4 axis.
- Ferrostatin-1 partially reversed triptolide's effects and alleviated TIC.
Conclusions:
- Triptolide-induced cardiotoxicity is mediated by ferroptosis through inactivation of the SLC7A11/GPX4 pathway.
- Targeting ferroptosis presents a potential therapeutic strategy to mitigate TIC.
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