PMID- 36635256
OWN - NLM
STAT- MEDLINE
DCOM- 20230116
LR  - 20230324
IS  - 2041-4889 (Electronic)
VI  - 14
IP  - 1
DP  - 2023 Jan 12
TI  - SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by 
      downregulating glutathione reductase.
PG  - 22
LID - 10.1038/s41419-023-05558-w [doi]
LID - 22
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Xu, Feng-Li
AU  - Xu FL
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Wu, Xiao-Hong
AU  - Wu XH
AD  - Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
FAU - Chen, Chang
AU  - Chen C
AD  - Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
FAU - Wang, Kai
AU  - Wang K
AUID- ORCID: 0000-0002-0137-1247
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Huang, Lu-Yi
AU  - Huang LY
AUID- ORCID: 0000-0002-0377-877X
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Xia, Jie
AU  - Xia J
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Liu, Yi
AU  - Liu Y
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Shan, Xue-Feng
AU  - Shan XF
AUID- ORCID: 0000-0002-3798-1792
AD  - Department of Pharmacy, The First Affiliated Hospital, Chongqing Medical 
      University, Chongqing, China. shanxuefeng@hospital.cqmu.edu.cn.
FAU - Tang, Ni
AU  - Tang N
AUID- ORCID: 0000-0001-5830-8786
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. 
      nitang@cqmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230112
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 1.8.1.7 (Glutathione Reductase)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (SLC27A5 protein, human)
RN  - 0 (Fatty Acid Transport Proteins)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Hepatocellular/drug therapy/genetics/metabolism
MH  - Sorafenib/pharmacology/therapeutic use
MH  - Glutathione Reductase/metabolism/pharmacology/therapeutic use
MH  - *Liver Neoplasms/drug therapy/genetics/metabolism
MH  - *Ferroptosis
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Drug Resistance, Neoplasm/genetics
MH  - Cell Line, Tumor
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - Fatty Acid Transport Proteins
PMC - PMC9837139
COIS- The authors declare no competing interests.
EDAT- 2023/01/13 06:00
MHDA- 2023/01/17 06:00
PMCR- 2023/01/12
CRDT- 2023/01/12 23:12
PHST- 2022/10/17 00:00 [received]
PHST- 2023/01/04 00:00 [accepted]
PHST- 2022/12/23 00:00 [revised]
PHST- 2023/01/12 23:12 [entrez]
PHST- 2023/01/13 06:00 [pubmed]
PHST- 2023/01/17 06:00 [medline]
PHST- 2023/01/12 00:00 [pmc-release]
AID - 10.1038/s41419-023-05558-w [pii]
AID - 5558 [pii]
AID - 10.1038/s41419-023-05558-w [doi]
PST - epublish
SO  - Cell Death Dis. 2023 Jan 12;14(1):22. doi: 10.1038/s41419-023-05558-w.