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SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity
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 a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225845/ https://www.ncbi.nlm.nih.gov/pubmed/35757509 http://dx.doi.org/10.1155/2022/3192607 |
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author | Liu, Xian Chen, Cheng Han, Dong Zhou, Wei Cui, Yaowen Tang, Xianglin Xiao, Chengrong Wang, Yuguang Gao, Yue |
author_facet | Liu, Xian Chen, Cheng Han, Dong Zhou, Wei Cui, Yaowen Tang, Xianglin Xiao, Chengrong Wang, Yuguang Gao, Yue |
author_sort | Liu, Xian |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9225845 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-92258452022-06-24 SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity Liu, Xian Chen, Cheng Han, Dong Zhou, Wei Cui, Yaowen Tang, Xianglin Xiao, Chengrong Wang, Yuguang Gao, Yue Oxid Med Cell Longev Research Article 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. Hindawi 2022-06-16 /pmc/articles/PMC9225845/ /pubmed/35757509 http://dx.doi.org/10.1155/2022/3192607 Text en Copyright © 2022 Xian Liu et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Liu, Xian Chen, Cheng Han, Dong Zhou, Wei Cui, Yaowen Tang, Xianglin Xiao, Chengrong Wang, Yuguang Gao, Yue SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title | SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title_full | SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title_fullStr | SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title_full_unstemmed | SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title_short | SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity |
title_sort | slc7a11/gpx4 inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225845/ https://www.ncbi.nlm.nih.gov/pubmed/35757509 http://dx.doi.org/10.1155/2022/3192607 |
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