SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase

作者全名："Xu, Feng-li; Wu, Xiao-hong; Chen, Chang; Wang, Kai; Huang, Lu-yi; Xia, Jie; Liu, Yi; Shan, Xue-feng; Tang, Ni"

作者地址："[Xu, Feng-li; Wang, Kai; Huang, Lu-yi; Xia, Jie; Liu, Yi; Tang, Ni] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China; [Wu, Xiao-hong; Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Shan, Xue-feng] Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing, Peoples R China"

通信作者："Tang, N (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China.; Shan, XF (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000913542700004

JCR分区：Q1

影响因子：8.1

年份：2023

卷号：14

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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."

基金机构："National Natural Science Foundation of China [81902856, 81872270]; Natural Science Foundation Project of Chongqing [cstc2019jscx-dxwtBX0019]; Science and Technology Research Program of Chongqing Municipal Education Commission [HZ2021006, KJZD-M202000401]; Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau); Innovative and Entrepreneurial Team of Chongqing Talents Plan; Future Medical Youth Innovation Team of Chongqing Medical University [W0036, W0101]; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University"

基金资助正文："This work was partially supported by the National Natural Science Foundation of China (grant no. 81902856, 81872270), the Natural Science Foundation Project of Chongqing (cstc2019jscx-dxwtBX0019), the Science and Technology Research Program of Chongqing Municipal Education Commission (HZ2021006, KJZD-M202000401), Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101), and the Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University."