SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase
Abstract Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05558-w |
| _version_ | 1797952350817615872 |
|---|---|
| author | Feng-li Xu Xiao-hong Wu Chang Chen Kai Wang Lu-yi Huang Jie Xia Yi Liu Xue-feng Shan Ni Tang |
| author_facet | Feng-li Xu Xiao-hong Wu Chang Chen Kai Wang Lu-yi Huang Jie Xia Yi Liu Xue-feng Shan Ni Tang |
| author_sort | Feng-li Xu |
| collection | DOAJ |
| description | Abstract Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27 member 5 (SLC27A5/FATP5), an enzyme involved in the metabolism of fatty acid and bile acid, is downregulated in sorafenib-resistant HCC. SLC27A5 deficiency facilitates the resistance towards sorafenib in HCC cells, which is mediated by suppressing ferroptosis. Further mechanism studies reveal that the loss of SLC27A5 enhances the glutathione reductase (GSR) expression in a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent manner, which maintains glutathione (GSH) homeostasis and renders insensitive to sorafenib-induced ferroptosis. Notably, SLC27A5 negatively correlates with GSR, and genetic or pharmacological inhibition of GSR strengthens the efficacy of sorafenib through GSH depletion and the accumulation of lipid peroxide products in SLC27A5-knockout and sorafenib-resistant HCC cells. Based on our results, the combination of sorafenib and carmustine (BCNU), a selective inhibitor of GSR, remarkably hamper tumor growth by enhancing ferroptotic cell death in vivo. In conclusion, we describe that SLC27A5 serves as a suppressor in sorafenib resistance and promotes sorafenib-triggered ferroptosis via restraining the NRF2/GSR pathway in HCC, providing a potential therapeutic strategy for overcoming sorafenib resistance. |
| first_indexed | 2024-04-10T22:44:56Z |
| format | Article |
| id | doaj.art-7b3437e5953646a1ac83373473e37db0 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T22:44:56Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-7b3437e5953646a1ac83373473e37db02023-01-15T12:22:40ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111410.1038/s41419-023-05558-wSLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductaseFeng-li Xu0Xiao-hong Wu1Chang Chen2Kai Wang3Lu-yi Huang4Jie Xia5Yi Liu6Xue-feng Shan7Ni Tang8Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityInstitute of Life Sciences, Chongqing Medical UniversityInstitute of Life Sciences, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityDepartment of Pharmacy, The First Affiliated Hospital, Chongqing Medical UniversityKey Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical UniversityAbstract Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27 member 5 (SLC27A5/FATP5), an enzyme involved in the metabolism of fatty acid and bile acid, is downregulated in sorafenib-resistant HCC. SLC27A5 deficiency facilitates the resistance towards sorafenib in HCC cells, which is mediated by suppressing ferroptosis. Further mechanism studies reveal that the loss of SLC27A5 enhances the glutathione reductase (GSR) expression in a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent manner, which maintains glutathione (GSH) homeostasis and renders insensitive to sorafenib-induced ferroptosis. Notably, SLC27A5 negatively correlates with GSR, and genetic or pharmacological inhibition of GSR strengthens the efficacy of sorafenib through GSH depletion and the accumulation of lipid peroxide products in SLC27A5-knockout and sorafenib-resistant HCC cells. Based on our results, the combination of sorafenib and carmustine (BCNU), a selective inhibitor of GSR, remarkably hamper tumor growth by enhancing ferroptotic cell death in vivo. In conclusion, we describe that SLC27A5 serves as a suppressor in sorafenib resistance and promotes sorafenib-triggered ferroptosis via restraining the NRF2/GSR pathway in HCC, providing a potential therapeutic strategy for overcoming sorafenib resistance.https://doi.org/10.1038/s41419-023-05558-w |
| spellingShingle | Feng-li Xu Xiao-hong Wu Chang Chen Kai Wang Lu-yi Huang Jie Xia Yi Liu Xue-feng Shan Ni Tang SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase Cell Death and Disease |
| title | SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| title_full | SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| title_fullStr | SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| title_full_unstemmed | SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| title_short | SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| title_sort | slc27a5 promotes sorafenib induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase |
| url | https://doi.org/10.1038/s41419-023-05558-w |
| work_keys_str_mv | AT fenglixu slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT xiaohongwu slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT changchen slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT kaiwang slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT luyihuang slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT jiexia slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT yiliu slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT xuefengshan slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase AT nitang slc27a5promotessorafenibinducedferroptosisinhepatocellularcarcinomabydownregulatingglutathionereductase |