PMID- 34623415
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220407
IS  - 1744-1358 (Electronic)
IS  - 0071-1365 (Linking)
VI  - 65
IP  - 7
DP  - 2021 Dec 22
TI  - Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of 
      Alzheimer's disease.
PG  - 925-940
LID - 10.1042/EBC20210017 [doi]
AB  - Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality and 
      emerging evidence indicates that ferroptosis has great explanatory potential for 
      neuronal loss and associated CNS dysfunction in a range of neurodegenerative 
      diseases (e.g., Alzheimer's, Parkinson's and Huntington's diseases, Motor neuron 
      disease, Friedreich ataxia (FRDA)). Ferroptotic death results from lethal levels 
      of phospholipid hydroperoxides that are generated by iron-dependent peroxidation 
      of polyunsaturated fatty acids (PUFAs), such as arachidonic and adrenic acids, 
      which are conjugated to specific phospholipids (e.g., phosphatidylethanolamines 
      (PEs)). The major cellular protector against ferroptosis is glutathione 
      peroxidase 4 (GPX4), a membrane-associated selenoenzyme that reduces deleterious 
      phospholipid hydroperoxides to their corresponding benign phospholipid alcohols 
      in a glutathione-dependent manner. Other complementary protective systems have 
      also been identified that act to bolster cellular defences against ferroptosis. 
      Many pharmacological modulators of the ferroptosis pathway have been identified, 
      targeting proteins involved in iron homoeostasis and autophagy; the production 
      and detoxification of lipid peroxides, and cyst(e)ine/glutathione metabolism. 
      While a growing number of cell signalling pathways converge to regulate the 
      ferroptosis cascade, an emerging understanding of ferroptosis regulation suggests 
      that the ferroptotic 'tone' of cells can be set by the transcription factor, 
      nuclear factor erythroid 2-related factor 2 (NRF2), which transcriptionally 
      controls many key components of the ferroptosis pathway. In this review, we 
      provide a critical overview of the relationship between ferroptosis and NRF2 
      signalling. With a focus on the role of ferroptosis in Alzheimer's disease (AD), 
      we discuss how therapeutic modulation of the NRF2 pathway is a viable strategy to 
      explore in the treatment of ferroptosis-driven neurodegeneration.
CI  - (c) 2021 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Lane, Darius J R
AU  - Lane DJR
AUID- ORCID: 0000-0001-8725-6903
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and 
      Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
FAU - Metselaar, Billie
AU  - Metselaar B
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and 
      Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
FAU - Greenough, Mark
AU  - Greenough M
AUID- ORCID: 0000-0001-6767-0584
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and 
      Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
FAU - Bush, Ashley I
AU  - Bush AI
AUID- ORCID: 0000-0001-8259-9069
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and 
      Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
FAU - Ayton, Scott J
AU  - Ayton SJ
AUID- ORCID: 0000-0002-3479-2427
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and 
      Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - Essays Biochem
JT  - Essays in biochemistry
JID - 0043306
RN  - 0 (Lipid Peroxides)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - *Alzheimer Disease/metabolism
MH  - *Ferroptosis
MH  - Humans
MH  - Lipid Peroxidation
MH  - Lipid Peroxides
MH  - NF-E2-Related Factor 2/metabolism
OTO - NOTNLM
OT  - Alzheimers disease
OT  - Ferroptosis
OT  - Nrf2
EDAT- 2021/10/09 06:00
MHDA- 2022/04/08 06:00
CRDT- 2021/10/08 12:20
PHST- 2021/07/14 00:00 [received]
PHST- 2021/08/26 00:00 [revised]
PHST- 2021/08/31 00:00 [accepted]
PHST- 2021/10/09 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/10/08 12:20 [entrez]
AID - 229898 [pii]
AID - 10.1042/EBC20210017 [doi]
PST - ppublish
SO  - Essays Biochem. 2021 Dec 22;65(7):925-940. doi: 10.1042/EBC20210017.