Evidence map›Paper›PMID 38317225›Full record

ArticleMolecular neurodegeneration2024

Microglial ferroptotic stress causes non-cell autonomous neuronal death.

Jeffrey R Liddell, James B W Hilton, Kai Kysenius, Jessica L Billings, Sara Nikseresht, Lachlan E McInnes, Dominic J Hare, Bence Paul, Stephen W Mercer, Abdel A Belaidi and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurodegeneration, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.

0numbers the graph read from it
0cells of the map it votes in
46citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

46 citing papers in PubMed.

  1. Review
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  3. LCN2-Driven Fibroblast Ferroptosis-Associated Injury Promotes Keratinocyte Proliferation via Lipid Peroxidation Signaling in Psoriasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
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  13. Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.Apoptosis : an international journal on programmed cell death · 2026
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Jeffrey R Liddell *Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia. jliddell@unimelb.edu.au.ORCID 0000-0002-0798-5338
James B W Hilton *Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.ORCID 0000-0002-2657-3566
Kai Kysenius *Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.ORCID 0000-0003-1038-2850
Jessica L BillingsDepartment of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Sara NiksereshtDepartment of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Lachlan E McInnesSchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia.
Dominic J HareAtomic Medicine Initiative, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Bence PaulSchool of Earth Science, The University of Melbourne, Parkville, VIC, 3010, Australia.
Stephen W MercerDepartment of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Abdel A BelaidiFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
Scott AytonFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
Blaine R RobertsDepartment of Biochemistry, Emory University, Atlanta, GA, 30322, USA.
Joseph S BeckmanLinus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA.
Catriona A McLeanAnatomical Pathology, Alfred Hospital, Melbourne, VIC, 3005, Australia.
Anthony R WhiteQIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
Paul S DonnellySchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia.
Ashley I BushFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
Peter J CrouchDepartment of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia. pjcrouch@unimelb.edu.au.ORCID 0000-0002-7777-4747

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundFerroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

methodsTo elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1

resultsWe found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1

conclusionsBy showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

Indexed as

Amyotrophic Lateral SclerosisNeurodegenerative DiseasesAnimalsCell DeathDisease Models, AnimalHumansMiceMicrogliaSuperoxide Dismutase-1Superoxide Dismutase-1Amyotrophic lateral sclerosis (ALS)Drug discoveryFerroptosisGliaGlial activationIronMicrogliaNeurodegenerationNeurotoxic astrocytesTherapy

Identifiers

PMID38317225
PMCPMC10840184

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.