PMID- 33931597
OWN - NLM
STAT- MEDLINE
DCOM- 20211005
LR  - 20211005
IS  - 2041-4889 (Electronic)
VI  - 12
IP  - 5
DP  - 2021 Apr 30
TI  - GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis 
      via inhibition of NRF2/GPX4 axis.
PG  - 426
LID - 10.1038/s41419-021-03718-4 [doi]
LID - 426
AB  - Increasing evidence supports that ferroptosis plays an important role in tumor 
      growth inhibition. Sorafenib, originally identified as an inhibitor of multiple 
      oncogenic kinases, has been shown to induce ferroptosis in hepatocellular 
      carcinoma (HCC). However, some hepatoma cell lines are less sensitive to 
      sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 
      (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression 
      of the master regulator of cellular redox homeostasis nuclear factor erythroid 
      2-related factor 2 (NRF2). This study aimed to investigate the role and 
      underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. 
      GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. 
      Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and 
      increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing 
      sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 
      inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted 
      ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the 
      combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC 
      progression in Gstz1(-/-) mice. In conclusion, this finding demonstrates that 
      GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in 
      HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a 
      promising strategy in HCC treatment.
FAU - Wang, Qiujie
AU  - Wang Q
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 - Bin, Cheng
AU  - Bin C
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 - Xue, Qiang
AU  - Xue Q
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Gao, Qingzhu
AU  - Gao Q
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, Ailong
AU  - Huang A
AUID- ORCID: 0000-0003-0148-7423
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. 
      ahuang@cqmu.edu.cn.
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. 
      wangkai@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 - 20210430
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antineoplastic Agents)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
RN  - EC 2.5.1.- (GSTZ1 protein, human)
RN  - EC 2.5.1.18 (Glutathione Transferase)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology
MH  - Ferroptosis
MH  - Glutathione Transferase/*metabolism
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/metabolism/pathology
MH  - NF-E2-Related Factor 2/*antagonists & inhibitors/metabolism
MH  - Phospholipid Hydroperoxide Glutathione Peroxidase/*antagonists & 
      inhibitors/metabolism
MH  - Sorafenib/*pharmacology
PMC - PMC8087704
COIS- The authors declare no competing interests.
EDAT- 2021/05/02 06:00
MHDA- 2021/10/06 06:00
PMCR- 2021/04/30
CRDT- 2021/05/01 05:59
PHST- 2021/01/03 00:00 [received]
PHST- 2021/04/15 00:00 [accepted]
PHST- 2021/04/15 00:00 [revised]
PHST- 2021/05/01 05:59 [entrez]
PHST- 2021/05/02 06:00 [pubmed]
PHST- 2021/10/06 06:00 [medline]
PHST- 2021/04/30 00:00 [pmc-release]
AID - 10.1038/s41419-021-03718-4 [pii]
AID - 3718 [pii]
AID - 10.1038/s41419-021-03718-4 [doi]
PST - epublish
SO  - Cell Death Dis. 2021 Apr 30;12(5):426. doi: 10.1038/s41419-021-03718-4.