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NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases
Open accessAbstract
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.
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Written from the paper’s full text.
TL;DR
NOX4 protein is elevated in impaired astrocytes in AD patient cortex and APP/PS1 mouse cortex, where lipid peroxidation markers 4-HNE and MDA are also increased. In human astrocytes, NOX4 overexpression impairs mitochondrial metabolism, induces oxidative stress and antioxidant suppression, and promotes ferroptosis-like lipid peroxidation and cytotoxicity.
Key findings
- NOX4 levels were significantly elevated in GFAP-positive impaired astrocytes in AD cortex versus non-AD cortex (n = 3 per group, n = 10 images per subject; p < 0.01) and in APP/PS1 mouse cortex versus WT (n = 5 per group, n = 10 images per subject; p < 0.01).
- Oxidative stress-induced lipid peroxidation markers 4-HNE and MDA were significantly elevated in impaired astrocytes of AD patients and APP/PS1 mice, and 4-HNE co-localized with NOX4-positive astrocytes (p < 0.01).
- In human astrocytes, NOX4 overexpression significantly suppressed basal and oligomycin/FCCP-responsive oxygen consumption rate, reduced mitochondrial ATP production, and reduced protein levels of all five mitochondrial ETC complexes: Complex I NDUFB8, Complex II SDHB, Complex III UQCRC2, Complex IV MTCO1, and Complex V ATP5F1A (p < 0.05 or p < 0.01).
- NOX4 overexpression increased mtROS and mitochondrial fragmentation, reduced GSH and GSH/GSSG, increased GSSG, inhibited NRF2 nuclear translocation and HO-1/GCL, and increased 4-HNE, MDA, iron accumulation, morphological cell death, and LDH cytotoxicity (p < 0.05 or p < 0.01).
Methods
- Postmortem human brain tissues: 12 paraffin-embedded tissues from 3 AD donors (frontal, occipital, temporal, parietal cortex) and 4 normal adult brain tissues from 4 donors; immunofluorescence analyzed NOX4, 4-HNE, MDA, GFAP, and Tomm20. APP/PS1 double-transgenic mice were compared with WT mice.
- Human astrocytes were transduced with pCMV6-AC-GFP-NOX4 or vector. Assays included Seahorse XF96e OCR and real-time ATP rate, immunoblot for mitochondrial ETC complexes, MitoSOX flow for mtROS, GSH/GSSG and GSSG measurements, NRF2 nuclear/cytosolic fractionation, HO-1 and GCL levels/activity, iron colorimetric assay, LDH cytotoxicity, and 3D imaging.
- Statistics used Shapiro-Wilk and Levene’s tests, two-tailed Student’s t-test for two groups, and ANOVA with Dunnett’s post hoc for multiple groups; significance was p < 0.05, p < 0.01, or p < 0.001.
Limitations
- Stated: it remains unclear whether the impaired astrocytes with high NOX4 have reactive astrocyte function in AD, and further study is needed on the role of NOX4 in reactive astrocytes. The authors also state that further study is needed to identify secreted molecules from NOX4-induced ferroptosis as potential diagnostic markers.
- Evident from the text: the human sample is small (3 AD donors and 4 normal donors), and the mechanistic causality in human astrocytes relies mainly on NOX4 overexpression; the text does not report NOX4 knockdown, NOX4 inhibition, or ferroptosis-blockade rescue experiments.
- Evident from the text: APP/PS1 mouse data are descriptive immunofluorescence comparisons, without in vivo NOX4 manipulation reported.
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58 Own result · 39 Not checked yet · 20 Own interpretation · 4 Own method · 1 Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”
- Also stated in: § Introduction · plain
“We found that the elevation of NOX4 promotes the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § Introduction · plain
“The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged
“These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of patients with AD.”
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain
“The levels of 4-HNE and MDA were generally higher in every individual patient with AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”
- Also stated in: § Introduction · plain
“The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD.”
- Also stated in: § Introduction · plain
“Here, our results showed that the levels of NOX4 were significantly elevated in impaired astrocytes in patients with AD and APP/PS1 double-transgenic mouse model of AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”
- Also stated in: § Introduction · plain
“The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes.”
- Also stated in: § Introduction · plain
“Notably, the elevation of NOX4 induced ferroptosis-dependent cytotoxicity by the activation of lipid peroxidation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § Introduction · plain
“The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, the number of impaired astrocytes which have the positive subcellular co-localization between NOX4 and GFAP was significantly increased in patients with AD (AD) (Fig. 1C).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 35
- It may state two separate claims as one. 5
Every source the paper cites for this claim was checked and supports it.
In the paper
“Similarly, a recent study has suggested that NOX4 in pericytes is the major source of ROS which is involved in the constriction of capillaries early in the response to Aβ [48].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Supportedcites [48] Nortley, 2019, Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes, Science source
The section “Reactive oxygen species and endothelin-1 generate the capillary constriction” explicitly says the data suggest that NOX4 in pericytes is the main generator of ROS involved in capillary constriction early in the response to Aβ. The citing sentence preserves that tentative wording. (LLM, conf=0.95)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the length of GFAP-positive filaments was shortened and the shape of GFAP-positive filaments showed shrinkage in astrocytes of patients with AD (AD) compared to non-AD donor (Normal) (Fig. 1A).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“NOX4 produces ROS constitutively [37].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [37] Serrander, 2007, NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation, Biochem. J. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The impairment of mitochondrial ETC activity in mitochondrial metabolism leads to an increase of reactive oxygen species (ROS) production which occurs mainly at Complex I and Complex III [31].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [31] Nemoto, 2000, Role for mitochondrial oxidants as regulators of cellular metabolism, Mol. Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Among NOX isoforms, NOX4 is a major isoform in astrocytes [36].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [36] Nayernia, 2014, New insights on NOX enzymes in the central nervous system, Antioxidants Redox Signal. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The excessive production of ROS and the activation of lipid peroxidation are linked to ferroptosis-dependent cell death [32,33].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [32] Stockwell, 2017, Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biol. Dis. Cell
- Not checked yetcites [33] Stockwell, 2020, The chemistry and biology of ferroptosis, Cell Chem Biol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are random, independent, normally distributed, and have a common variance.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of supportive function by impaired astrocytes has been implicated in neurodegenerative diseases via neuronal death [21,22].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [21] Phatnani, 2015, Astrocytes in neurodegenerative disease, Cold Spring Harb Perspect Biol source
- Not checked yetcites [22] Karkkainen, 2012, Brain environment and Alzheimer's disease mutations affect the survival, migration and differentiation of neural progenitor cells, Curr. Alzheimer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Recent studies suggest that oxidative stress is a critical factor that contributes to the initiation and progression of AD [[2], [3], [4]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [[2], [3], [4]]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mitochondrial dysfunction plays an important role in the pathogenesis of AD as an early feature of AD [5,6].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [5] Perez Ortiz, 2019, Mitochondrial dysfunction in Alzheimer's disease: role in pathogenesis and novel therapeutic opportunities, Br. J. Pharmacol. source
- Not checked yetcites [6] Wood, 2020, Mitochondrial dysfunction manifests in the early stages of Alzheimer disease, Nat. Rev. Neurol.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Recent studies have shown the impairment of mitochondrial metabolism by multiple mitochondrial alterations in major neurodegenerative diseases such as AD and Parkinson's disease (PD) [[11], [12], [13]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [[11], [12], [13]]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mitochondrial damage has been found to be involved in lipid peroxidation and imbalance of iron homeostasis in neurodegenerative diseases such as AD and PD [34].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [34] Conrad, 2018, Regulation of lipid peroxidation and ferroptosis in diverse species, Genes Dev. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“To ensure objectivity, all measurements were performed with blinded conditions by two observers per experiment under identical conditions.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Immunofluorescence analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“NOX4 is linked to oxidative stress and ROS production in brain injury [42,43].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [42] Casas, 2017, NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage, Proc. Natl. Acad. Sci. U. S. A. source
- Not checked yetcites [43] Ma, 2018, Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury, Free Radic. Biol. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondrial dysfunction has been associated with the pathogenesis of AD [5,6].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [5] Perez Ortiz, 2019, Mitochondrial dysfunction in Alzheimer's disease: role in pathogenesis and novel therapeutic opportunities, Br. J. Pharmacol. source
- Not checked yetcites [6] Wood, 2020, Mitochondrial dysfunction manifests in the early stages of Alzheimer disease, Nat. Rev. Neurol.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Oxidative stress is linked to amyloid-beta (Aβ) toxicity in AD [44,45].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The levels of cerebral blood (CBF) and cerebral metabolic rate for oxygen (CMRO2) in the medial temporal region were decreased in patient with AD [38].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [38] Ishii, 1996, Decreased medial temporal oxygen metabolism in Alzheimer's disease shown by PET, J. Nucl. Med.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In APP/PS1 mouse model of AD, the elevation of NOX activity is linked to cognitive impairment [47].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [47] Bruce-Keller, 2011, Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation, Neurobiol. Dis. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Since NOX4 is a constitutively active form among the NOX isoforms, the activity of NOX4 depends on its expression [37].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [37] Serrander, 2007, NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation, Biochem. J. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“the high levels of ceramide contribute to formation of amyloid β-peptides [[81], [82], [83]]”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [81], [82], [83]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“the role of lipid peroxidation has been discovered in cell dysfunction and death during neuronal degeneration [74,75]”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [74] Mattson, 1998, Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity, Trends Neurosci. source
- Not checked yetcites [75] Keller, 1998, Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system, Rev. Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“High levels of 4-HNE found in pathological conditions or diseases which are associated with cellular stress and dysfunction, cellular damage and pro-apoptotic signaling [[68], [69], [70], [71], [72], [73]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [68], [69], [70]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Ferroptosis-derived dead cells can release damage-associated molecular patterns (DAMPs) and lipid metabolites that can cause an elevation of inflammation [76,77].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Reactive aldehydes from lipid peroxidation have biological active functions [59].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [59] Esterbauer, 1991, Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes, Free Radic. Biol. Med. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The high production of ROS is associated with excessive intracellular lipid accumulation such as diacylglycerol (DAG) and ceramide [[78], [79], [80]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [78], [79], [80]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A previous study has shown that a product of lipid peroxidation is increased in brain of patients with AD [55].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [55] Markesbery, 1998, Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease, Neurobiol. Aging source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The role of reactive astrocytes remains unclear in terms of plaque formation, Aβ clearance and plaque growth restriction [50,51].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Also, mitochondrial dysfunction including the excessive production of mtROS contributes to the induction of neuronal apoptosis [[84], [85], [86]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [84], [85], [86]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For immunoblots, β-actin was used as a loading control.”
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
“For immunoblots, Histone H3 (nuclear) and β-actin (cytosolic) was used as a loading control.”
- Also stated in: § NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation in human astrocytes · plain
“For immunoblots, β-actin was used as a loading control.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
In the paper
“The redox imbalance and oxidative stress are linked to neurodegeneration in AD [[1], [2], [3], [4]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [1], [2], [3]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the accumulation of ceramide may have the effects of neurotoxicity in AD”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are representative of three independent experiments.”
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
“Data are representative of three independent experiments.”
- Also stated in: § The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes · plain
“Data are representatives of three independent experiments.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
In the paper
“4-HNE, an electrophilic lipid peroxidation product, also has various cytotoxic effects of lipid peroxidation such as depletion of glutathione, dysfunction of structural proteins, reduction in enzyme activities, and induction of cell death [60].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [60] Craighead, 1995
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Based on hormetic effects of 4-HNE, low physiological levels of 4-HNE can provide positive effects on cell function including cell proliferation and signaling pathway such as tyrosine kinase receptor (TKR) activation and downstream kinase signaling [[61], [62], [63], [64], [65], [66], [67]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [61], [62], [63]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In pathogenesis of neurodegenerative diseases, the high levels of 4-HNE are involved in oxidative stress of AD or Parkinson's diseases [[70], [71], [72], [73]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [70], [71], [72]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The abundant diffusible products of lipid peroxidation are chemically reactive aldehydes including malondialdehyde (MDA), acrolein, 4-hydroxy-2-hexenal (4-HHE), and 4-hydroxy-2-nonenal (4-HNE) [57,58].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [57] Schneider, 2001, Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals, J. Biol. Chem. source
- Not checked yetcites [58] Porter, 1995, Mechanisms of free radical oxidation of unsaturated lipids, Lipids source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Regarding the form of astrocytes, reactive astrocytes are an activated form of astrocytes in response to toxic materials [49].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [49] Wilhelmsson, 2006, Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury, Proc. Natl. Acad. Sci. U. S. A. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The mechanisms by which NOX4 regulates ferroptosis of astrocytes by oxidative stress via impairment of mitochondrial metabolism in AD remain unclear.
“However, the mechanisms by which NOX4 regulates ferroptosis of astrocytes by oxidative stress via impairment of mitochondrial metabolism in AD remains unclear.”
The paper relies on this without support.
4-HNE is a marker for ferroptosis.
“Since the levels of 4-HNE, a marker for ferroptosis, were elevated in impaired astrocytes of patients with AD”
The paper relies on this without support.
Iron accumulation is a specific marker of ferroptosis.
“the accumulation of iron, a specific marker of ferroptosis”
The paper relies on this without support.
APP/PS1 mice model AD.
“APP/PS1 double-transgenic mouse model of AD”
The paper relies on this without support.
NRF2 is a key regulator of the cellular antioxidant response.
“nuclear factor erythroid 2–related factor 2 (NRF2) signaling pathway, a key regulator of the cellular antioxidant response”
The paper relies on this without support.
HO-1 and GCL are target genes of NRF2.
“heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2”
The paper relies on this without support.
Mitochondrial fragmentation indicates mitochondrial impairment.
“We next analyzed morphological impairment of mitochondria caused by NOX4 over-expression through immunofluorescence staining with Tomm20”
The paper relies on this without support.
The upstream molecular target in the regulation of ferroptosis by lipid peroxidation in Alzheimer's disease remains unclear.
“the upstream molecular target in the regulation of ferroptosis by lipid peroxidation in AD remains unclear”
The paper relies on this without support.
NOX4 levels are high in the cortex of patients with Alzheimer's disease.
“the high levels of NOX4, in cortex of patients with AD”
The paper relies on this without support.
It is unclear whether impaired astrocytes in Alzheimer's disease have a function of reactive astrocytes.
“it was unclear whether these impaired astrocytes have a function of reactive astrocytes in AD”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The levels of two products of oxidative damage, 4-HNE and MDA, were also significantly elevated, suggesting that the elevation of NOX4 promotes the impairment of mitochondrial metabolism, mitochondrial ROS production and fragmentation in human astrocytes [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
In the citing paper
“Ferroptosis-dependent cytotoxicity induced by the activation of OS has also been described in human astrocytes from AD patients [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
In the citing paper
“NO X4 is the astrocytes isoform, and its levels are reported significantly elevated in astrocytes of patients with AD and APP/PS1 double-transgenic mouse model of AD [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Human subjects study
“A total of four paraffin embedded adult normal brain tissues from four donors including frontal cortex (NBP2-77761), occipital cortex (NBP2-77766), temporal cortex (NBP2-77774) and parietal cortex (NBP2-77769) were obtained from Novus Biologicals”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
“(B) Quantification of intensity for NOX4 positive staining in astrocytes from immunofluorescence images in the cerebral cortex region from patients with AD (AD #1, AD #2, AD #3) or non-AD (normal) (n = 3 per group, n = 10 images per individual subject).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Reagents and antibodies
“polyclonal rabbit anti-4-HNE antibody (ab3517, Abcam, Cambridge, UK)”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Immunofluorescence analysis
“polyclonal rabbit anti-4-HNE antibody (1:100) (ab46545, Abcam, Cambridge, UK)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
“(G) Quantification of cells with mitochondrial fragmentation from immunofluorescence images of mitochondrial morphology in control (Control) and NOX4 overexpressing (NOX4) human astrocytes (n = 10 per group).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
“(The percent of morphological dead cells in a total of 100 cells of 10 individual images per group was calculated).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from brains of APP/PS1 mice
“Immunofluorescence staining revealed that the intensity of 4-HNE-positive staining in GFAP-positive astrocytes was increased of the cortex region of APP/PS1 mice compared to WT mice (Fig. 4A and C and Fig. S6).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from brains of APP/PS1 mice
“(B) Quantification of 4-HNE positive staining in astrocytes from immunofluorescence images in the cortex region from brains of APP/PS1 mice (APP/PS1) or wild-type mice (WT) (n = 5 per group, n = 10 images per individual subject). Data are mean ± standard deviation (SD). **, p < 0.01 by Student's two-tailed t-test. (C) Quantification of 4-HNE positive astrocytes”
Citations
Cites
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695 · cited 2×
“Ferroptosis is a type of programmed cell death that is dependent on iron and the accumulation of lipid peroxides, mainly lipid hydroperoxides, which cause damage to the lipid bilayer of the plasma membrane through accelerated oxidation of membrane lipids [32,33].”
BackgroundThe NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989 · cited 3×
“In most mammals, there are seven NOX isoforms (NOX1, NOX2, NOX3, NOX4, NOX5, dual oxidase (DUOX)1, and DUOX2) [35].”
BackgroundInfluentialChemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90192-6 · Cited by 6,672
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
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Oxidative Stress, Glutamate, and Neurodegenerative Disorders
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
Neurodegenerative diseases and oxidative stress
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“As the driving force of ferroptosis, a high level of lipid peroxidation can disrupt cellular function [56].”
BackgroundOxidative stress hypothesis in Alzheimer’s disease
Markesbery, W. R. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00629-6 · Cited by 2,383 · cited 1×
“Oxidative stress is characterized by the over-production of reactive oxygen species (ROS), damage of the mitochondrial respiratory chain, and imbalance of Ca2+ homeostasis [9,10].”
Background
Research works printed but not linked: 1
- Stockwell, 2017, Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biol. Dis. Cell, 171, 273
Cited by
Sorted by citations
Iron Homeostasis and Ferroptosis in Human Diseases: Mechanisms and Therapeutic Prospects
Ru, Q., Li, Y., Chen, L., Wu, Y., Min, J., & Wang, F. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01969-z · Cited by 724
The diversified role of mitochondria in ferroptosis in cancer
Liu, Y., Lu, S.-P., Wu, L., Yang, L., Wang, J., & Wang, J. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06045-y · Cited by 486
“In this case, NOX4 promoted the ferroptosis of astrocytes via oxidative stress-induced lipid peroxidation induced after mitochondrial metabolism was dysregulated [124].”
BackgroundOxidative Stress: Signaling Pathways, Biological Functions, and Disease
Liu, S., Liu, J., Wang, Y., Deng, F., & Deng, Z. (2025) · MedComm · doi:10.1002/mco2.70268 · Cited by 485
Cheng, X. M., Huang, J., Li, H., Zhao, D. S., Liu, Z., Zhu, L., Zhang, Z., & Peng, W. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154887 · Cited by 298
Ferroptosis: principles and significance in health and disease
Chen, F., Kang, R., Tang, D., & Liu, J. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01564-3 · Cited by 341
“Oxidation product Broad-spectrum cell lines, in vivo model [19, 409, 412, 413] MDA Oxidation product Broad-spectrum cell lines, in vivo model [53, 390, 414, 415] 8OHdG Oxidation product Broad-spectrum cell lines, in vivo model [170, 416, 417] DCN Protein HT-1080, PANC-1, Bx-PC3 and NCI-H460 cell…”
BackgroundOxidative stress and mitochondrial impairment: Key drivers in neurodegenerative disorders
Wen, P., Sun, Z., Gou, F., Wang, J., Fan, Q., Zhao, D., & Yang, L. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102667 · Cited by 253
The mechanism of ferroptosis and its related diseases
Feng, S., Tang, D., Wang, Y., Li, X., Bao, H., Tang, C., Dong, X., Li, X., Yang, Q., Yan, Y., et al. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00142-2 · Cited by 241
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“Oxidative stress is closely related to ferroptosis because of similar pathological process, and the crosstalk between of oxidative stress and ferroptosis has been studied in some diseases, including ischemic stroke and Alzheimer’s disease [29,30].”
BackgroundYang, X., Chen, Y., Guo, J., Li, J., Zhang, P., Yang, H., Rong, K., Zhou, T., Fu, J., & Zhao, J. (2023) · Advanced Science · doi:10.1002/advs.202207216 · Cited by 194
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NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors
Cipriano, A., Viviano, M., Feoli, A., Milite, C., Sarno, G., Castellano, S., & Sbardella, G. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00770 · Cited by 208
Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?
Wang, F., Wang, J., Shen, Y., Li, H., Rausch, W., & Huang, X. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.830569 · Cited by 180
Oxidative stress and regeneration
Jaganjac, M., Milković, L., Žarković, N., & Žarković, K. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.02.004 · Cited by 162
Wang, Y., Wu, S., Li, Q., Sun, H., & Wang, H. (2023) · Advanced Science · doi:10.1002/advs.202300325 · Cited by 171
Ferroptosis: a double-edged sword mediating immune tolerance of cancer
Dang, Q., Sun, Z., Wang, Y., Wang, L., Liu, Z., & Han, X. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05384-6 · Cited by 155
TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells
Li, K., Chen, B., Xu, A., Shen, J.-L., Li, K., Hao, K., Hao, R., Yang, W. J., Jiang, W., Zheng, Y., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102451 · Cited by 141
Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential
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“Mitochondrial dysfunction plays a vital role in intracellular iron metabolism disorder and accumulation of ROS, thus providing materials for ferroptosis (78).”
BackgroundPathological phenotypes of astrocytes in Alzheimer’s disease
Kim, J., Yoo, I. D., Lim, J., & Moon, J. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01148-0 · Cited by 154
“In a study on the ferroptosis of astrocytes in AD patients, ferroptosis-related oxidative stress markers, including 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), were elevated in astrocytes of the cerebral cortex of brains of AD patients 38 .”
BackgroundInfluentialSelf-citationThe interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L., & Peng, W. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00397-x · Cited by 156
“Park et al. reported that an increase in NADPH oxidase-4 level aggravates oxidative stress in human astrocytes through the production of mitochondrial ROS, fragmentation of mitochondria and suppression of cellular antioxidant mechanisms, thereby enhancing the ferroptosis of astrocytes [126].”
BackgroundTargeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders
Li, J., Jia, B., Cheng, Y., Song, Y., Li, Q., & Luo, C. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/3999083 · Cited by 136
“In patients with AD and a mouse model of AD, NADPH oxidases 4 (NOX4) causes lipid peroxidation and promotes ferroptosis of astrocytes via the damage of mitochondrial metabolism in AD [81].”
Luo, X., Wang, Y., Zhu, X., Chen, Y., Xu, B., Bai, X., Weng, X., Xu, J., Tao, Y., Yang, D., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102987 · Cited by 128
“There is increasing evidence that excessive oxidative stress induced lipid peroxidation is primarily responsible for the progression of fer-roptosis [65 – 67].”
BackgroundMitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis
Qu, K., Fang, Y., Qin, X., Zhang, K., He, W., Dong, M., & Wu, G. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1084604 · Cited by 129
Sun, Q., Xing, X., Wang, H., Wan, K., Fan, R., Liu, C., Wang, Y., Wu, W., Wang, Y., & Wang, R. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115586 · Cited by 125
ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis
Yang, Z., Zou, S., Zhang, Y., Zhang, J., Zhang, P., Xiao, L., Xie, Y., Meng, M., Feng, J., Kang, L., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39901-8 · Cited by 124
Zhou, R., Chen, Y., Li, S., Wei, X., Hu, W., Tang, S., Ding, J., Fu, W., Zhang, H., Chen, F., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102411 · Cited by 115
Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases
Wang, Y., Lv, M.-N., & Zhao, W. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102035 · Cited by 122
Chen, Y., Meng, Z., Li, Y., Liu, S., Hu, P. L., & Luo, E. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00905-9 · Cited by 132
Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection
Lee, K. H., Cha, M., & Lee, B. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413315 · Cited by 104
“NOX4, but not NOX2, is expressed in astrocytes, and even a low expression of NOX4 regulates oxidative stress in astrocytes [44,45].”
BackgroundLi, J., Wang, L., Wang, B., Zhang, Z., Jiang, L., Qin, Z., Zhao, Y., & Su, B. (2023) · Theranostics · doi:10.7150/thno.81240 · Cited by 102
“Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is a constitutive enzyme expressed in the kidney and primarily contributes to the growth in reactive oxygen species (ROS) [6], and exerts a pivotal part in the modulation of oxidative stress and downstream signals [7-10].”
Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice
Li, X., Chen, J., Feng, W., Wang, C., Chen, M., Li, Y., Chen, J., Liu, X., Liu, Q., & Tian, J. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154962 · Cited by 101
Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases
Xiang, Y., Song, X., & Long, D. (2024) · Archives of Toxicology · doi:10.1007/s00204-023-03660-8 · Cited by 116
Targeting ferroptosis as a vulnerability in pulmonary diseases
Yang, L., Cao, L., Zhang, X., & Chu, B. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05070-7 · Cited by 101
“Moreover, reactive toxic aldehydes among lipid peroxidation products such as 4-hydroxy2-nonenal (4-HNE) or malondialdehyde (MDA) are confirmed as markers of oxidative stress-induced lipid peroxidation [17, 18].”
BackgroundFocusing on mitochondria in the brain: from biology to therapeutics
Song, N., Mei, S., Wang, X.-X., Hu, G., & Lu, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00409-w · Cited by 111
Ferroptosis and Its Role in Chronic Diseases
Hu, W., Liang, K., Zhu, H., Zhao, C., Hu, H., & Yin, S. (2022) · Cells · doi:10.3390/cells11132040 · Cited by 94
“NADPH oxidase 4 promotes astrocytes ferroptosis via oxidative-stress-induced lipid peroxidation in AD [147].”
BackgroundMitochondrial dysfunction in chronic neuroinflammatory diseases (Review)
Qin, P., Sun, Y., & Li, L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5371 · Cited by 106
“For instance, lipid peroxidation engenders the production of harmful byproducts such as malo‑ ndialdehyde and 4‑hydroxynonenal, intensifying the oxidative stress milieu (84).”
BackgroundBoonpraman, N., Yoon, S., Kim, C. Y., Moon, J., & Yi, S. S. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102698 · Cited by 95
Self-citationDeng, X., Lin, B., Wang, F., Xu, P., & Wang, N. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.155282 · Cited by 100
Li, X., Song, J.-W., Zhang, Z.-Z., Zhang, M.-W., Liang, L., Miao, R., Liu, Y., Chen, Y., Liu, X.-Y., & Zhong, J. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.10.320 · Cited by 89
The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders
Xu, Y., Jia, B., Li, J., Li, Q., & Luo, C. (2024) · Antioxidants · doi:10.3390/antiox13040395 · Cited by 92
“Notably, NADPH oxidase 4 (NOX4) in astrocytes catalyzes the production of reactive oxygen species (ROS), further promoting neuroin-flammation and mitochondrial damage [215].”
BackgroundMitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications
Feng, F., He, S., Li, X., He, J., & Luo, L. (2023) · Aging and Disease · doi:10.14336/ad.2023.0717 · Cited by 92
“…mitochondrial metabolism due to the suppression of mitochondrial respiration and ATP synthesis, the inhibition of cellular antioxidant activity, and the induction of ferroptosis in human astrocytes[206] has been shown to contribute to increased NOX4 levels, which in turn promotes oxidative stress.”
BackgroundDang, Y., He, Q. H., Yang, S., Sun, H., Liu, Y., Li, W., Tang, Y., Zheng, Y., & Wu, T. (2022) · Pharmaceuticals · doi:10.3390/ph15101177 · Cited by 82
“They were then washed with PBS and observed using THUNDER Imaging Systems (Leica Microsystems, Wetzlar, Germany) [32].”
BackgroundMethodInfluentialZooming in and out of ferroptosis in human disease
Wang, X., Zhou, Y., Min, J., & Wang, F. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-0992-z · Cited by 85
Oxygen metabolism abnormality and Alzheimer's disease: An update
Liu, G., Yang, C., Wang, X., Chen, X., Wang, Y., & Le, W. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102955 · Cited by 87
“Park et al. represented that overexpression of NOX4 inhibits ATP production, thereby significantly increasing mitochondrial metabolic damage and promoting ferroptosis in AD astrocytes [114].”
BackgroundOxidative stress–mediated neuroinflammation in Alzheimer’s disease
Firdous, S. M., Khan, S. A., & Maity, A. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03188-3 · Cited by 90
“Furthermore, NOX4-mediated ferroptosis in human astrocytes has been duly documented in a study conducted (Park et al. 2021).”
Zhang, S., Xu, J., Si, H., Wu, Y., Zhou, S., & Shen, B. (2022) · Antioxidants · doi:10.3390/antiox11091668 · Cited by 85
“In ferroptosis, MDA and 4-HNE are reliable markers of oxidative stress-induced lipid peroxidation in cancer [28], AD [29], and acute lung injury [30].”
BackgroundOrganelle-Specific Mechanisms in Crosstalk between Apoptosis and Ferroptosis
Wu, P., Zhang, X., Duan, D., & Жао, Л. (2023) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2023/3400147 · Cited by 92
“Both apoptosis and ferroptosis induce mitochondrial dysfunction in ETC, which results in reduced ATP levels and excess ROS production [48, 68].”
BackgroundNOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration
Liu, R., Wang, J., Chen, Y., Collier, J. M., Capuk, O., Jin, S., Sun, M., Mondal, S. K., Whiteside, T. L., Stolz, D. B., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04831-8 · Cited by 83
“NOX4 is the major source of ROS during brain damage, and it is the predominant isoform expressed by astrocytes [39, 40].”
BackgroundXie, Z., Wang, X., Luo, X., Yan, J., Zhang, J., Sun, R., Luo, A., & Li, S. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115374 · Cited by 88
Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease
Xu, C., Liu, Z., & Xiao, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212403 · Cited by 78
Da, Z., Yang, K., Guo, H., Zeng, J., Wang, S., Xu, H., Ge, A., Zeng, L., Chen, S., & Ge, J. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114312 · Cited by 77
Adipocyte-derived ferroptotic signaling mitigates obesity
Wang, X., Wu, Q., Zhong, M., Chen, Y., Wang, Y., Li, X., Zhao, W., Ge, C., Wang, X., Yu, Y., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.11.010 · Cited by 81
Oxidative Stress and Skin Diseases: The Role of Lipid Peroxidation
Pomi, F. L., Gammeri, L., Borgia, F., Gioacchino, M. D., & Gangemi, S. (2025) · Antioxidants · doi:10.3390/antiox14050555 · Cited by 76
“OS contributes to the genesis and the maintenance of chronic inflammatory processes, as well as neurodegenerative processes such as Alzheimer’s dis‑ ease [13] and Parkinson’s disease [14].”
Ferroptosis: mechanisms and therapeutic targets
Zhou, Q., Meng, Y., Le, J., Sun, Y., Dian, Y., Yao, L., Xiong, Y., Zeng, F., Chen, X., & Deng, G. (2024) · MedComm · doi:10.1002/mco2.70010 · Cited by 89
Gut microbiota bridges the iron homeostasis and host health
Xiao, L., Tang, R., Wang, J., Wan, D., Yin, Y., & Xie, L. (2023) · Science China Life Sciences · doi:10.1007/s11427-022-2302-5 · Cited by 70
Role of mitochondria in the regulation of ferroptosis and disease
Fu, C., Cao, N., Zeng, S., Zhu, W., Fu, X., Liu, W., & Fan, S. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1301822 · Cited by 71
“For instance, in Alzheimer’s disease, NADPH Oxidase 4 (NOX4) promotes ferroptosis in astrocytes by inducing oxidative stress-induced lipid peroxidation and impairing mitochondrial metabolism (95).”
BackgroundFerroptosis in ulcerative colitis: Potential mechanisms and promising therapeutic targets
Long, D., Mao, C., Huang, Y., Xu, Y., & Zhu, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116722 · Cited by 81
Xie, J., Lv, H., Liu, X., Xia, Z., Li, J., Hong, E., Ding, B., Zhang, W., & Chen, Y. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.02.015 · Cited by 68
Ye, Y., Jiang, M., Hong, X., et al. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c02027 · Cited by 67
Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches
Cai, K., Jiang, H., Zou, Y., Song, C., Cao, K., Chen, S., Wu, Y., Zhang, Z., Geng, D., Zhang, N., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107281 · Cited by 71
Long, Q., Li, T., Zhu, Q., He, L., & Zhao, B.-B. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117679 · Cited by 67
Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors
Punziano, C., Trombetti, S., Cesaro, E., Grosso, M., & Faraonio, R. (2024) · Antioxidants · doi:10.3390/antiox13030298 · Cited by 75
Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm
Wang, Y., Ge, M., Wang, J., Xu, Y., Wang, N., & Xu, S. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08114-w · Cited by 83
“Precision through metabolic phenotyping MRIS is dynamically remodeled by comorbidities, aging, and genetic variation, necessitating biomarker-driven strati fi cation [85 – 96].”
A quantitative meta-analysis of vitamin C in the pathophysiology of Alzheimer’s disease
Hamid, M., Mansoor, S., Amber, S., & Zahid, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.970263 · Cited by 67
“It is also noteworthy that NADPH oxidase 4 (NOX4) mediates the ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation through the impairment of mitochondrial metabolism in AD (Park et al., 2021).”
BackgroundWang, M., Tang, G., Zhou, C., Guo, H., Hu, Z., Hu, Q., & Li, G. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110387 · Cited by 62
Iron metabolism mediates microglia susceptibility in ferroptosis
Jiao, L., Li, X., Luo, Y., Wei, J., Ding, X., Xiong, H., Liu, X., & Lei, P. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.995084 · Cited by 68
“It has been reported that ferroptosis also occurred in astrocytes and microglia during neurodegenerative conditions, and inhibition of its activation in astrocytes can prevent neuronal death (Ishii et al., 2019; Kapralov et al., 2020; Park et al., 2021).”
BackgroundOxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis
Fujii, J., & Imai, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147544 · Cited by 65
“The activation of NOX4 promotes ferroptosis of astrocytes via the impairment of mitochondrial metabolism and the production of lipid peroxides, which may be associated with Alzheimer’s disease [191].”
BackgroundThe potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health
Qiao, L., Yang, G., Wang, P., & Xu, C. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107434 · Cited by 73
Zhou, J., Zhang, Y., Wu, J., Qiao, M., Xu, Z., Peng, X., & Mei, S. (2021) · Journal of Proteomics · doi:10.1016/j.jprot.2021.104235 · Cited by 61
The role of ferroptosis in neurodegenerative diseases
Fei, Y., & Ding, Y. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1475934 · Cited by 69
Liu, Q., Wang, X., Hu, Y., Zhao, J.-N., Huang, C.-H., Li, T., Zhang, B.-G., He, Y., Wu, Y.-Q., Zhang, Z.-J., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102697 · Cited by 58
Ferroptosis: a new hunter of hepatocellular carcinoma
Jiang, Y., Yu, Y., Pan, Z., Glandorff, C., & Sun, M. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01863-1 · Cited by 70
“Simultaneously, they modulate ferroptosis through ROS and may impact iron metabolism [74 – 76].”
BackgroundLi, H., Tan, Y., Cheng, X. M., Zhang, Z., Huang, J., Hui, S., Zhu, L., Liu, Y., Zhao, D. S., Liu, Z., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.990307 · Cited by 77
“Accumulating evidence shows that the AD brain is under extensive oxidative stress (Park et al., 2021; Plascencia-Villa and Perry, 2021; Tamagno et al., 2021) and that methionine is recognized as an important antioxidant (Moskovitz et al.”
BackgroundTang, Z., Chen, Z., Guo, M., Peng, Y., Xiao, Y. C., Guan, Z.-Z., Ni, R., & Qi, X. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04023-9 · Cited by 60
“High levels of 4-HNE are involved in the oxidative stress of AD or Parkinson’s disease (PD), associated with cellular stress and pro-apoptosis [24].”
InfluentialPotential therapeutic use of plant flavonoids in AD and PD
Meng-zhen, S., Ju, L., Zhang, L., Cai-feng, D., Shu-da, Y., Hao-fei, Y., & Wei-yan, H. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e11440 · Cited by 56
“Oxidative stress induces lipid peroxidation and damages nucleic acids and proteins [38].”
BackgroundFerroptosis mechanism and Alzheimer's disease
Feng, L., Sun, J. J., Xia, L., Shi, Q., Hou, Y., Zhang, L., Li, M., Fan, C., & Sun, B. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.389362 · Cited by 56
Zhang, W., Ding, L., Chen, H., Zhang, M., Ma, R., Zheng, S., Gong, J., Zhang, Z., Xu, H., Xu, P., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05807-y · Cited by 55
Quercetin protects rat BMSCs from oxidative stress via ferroptosis
Lan, D., Qi, S., Yao, C. H., Li, X., Liu, H., Wang, D. M., & Wang, Y. (2022) · Journal of Molecular Endocrinology · doi:10.1530/jme-22-0086 · Cited by 51
The role of ferroptosis mediated by Bmal1/Nrf2 in nicotine -induce injury of BTB integrity
Zhang, Z., Cheng, J., Li, Y., Li, X., Hua, R., Xu, D., Jiang, Z., & Li, Q. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.02.024 · Cited by 49
Li, B., Wu, C., Li, Z., et al. (2024) · ACS Nano · doi:10.1021/acsnano.4c10012 · Cited by 49
Shao, Y., Jia, H., Li, S., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/7007933 · Cited by 48
Wang, Q.-H., Liu, J., Zhang, Y., Li, Z., Zhao, Z., Jiang, W., Zhao, J., Hou, L.-Y., & Wang, Q.-S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103369 · Cited by 49
“Increased levels of lipid peroxidation product MDA and 4-HNE, an oxidative stress-induced lipid peroxidation marker [52], were observed in rotenone-treated WT mice in comparison to WT vehicle controls (Fig.”
ResultA Concise Review on Oxidative Stress-Mediated Ferroptosis and Cuproptosis in Alzheimer’s Disease
Huang, X. (2023) · Cells · doi:10.3390/cells12101369 · Cited by 47
“These data suggest that NOX4 promotes the ferroptosis of astrocytes by oxidative-stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD [43].”
BackgroundXiong, F., Gong, K., Xu, H., Tu, Y., Lu, J., Zhou, Y., He, W., Li, W., Li, C., Zhao, L., et al. (2022) · Journal of Advanced Research · doi:10.1016/j.jare.2022.02.011 · Cited by 47
“Disrupted lipid metabolism is intertwined with lipid peroxidation and oxidative stress, and ultimately destroys cellular membrane structure and causes cell apoptosis and necrosis [35,36].”
BackgroundRole of NADPH Oxidases in Blood–Brain Barrier Disruption and Ischemic Stroke
Hernandes, M. S., Xu, Q., & Griendling, K. K. (2022) · Antioxidants · doi:10.3390/antiox11101966 · Cited by 47
“Nox4 is highly expressed in neurons [40], and has been found to be present in astrocytes [41], microglia [42], pericytes [43], and brain endothelial cells [40] (Figure 1).”
BackgroundLi, Y., Peng, Y., Yang, Y., Shi, T., Liu, R., Luan, Y., & Yin, C. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155423 · Cited by 46
“Excessive oxidative stress has the potential to cause elevated levels of lipid peroxides, thus facilitating ferroptotic demise (Park et al., 2021).”
Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer’s Disease
Singh, R., Panghal, A., Jadhav, K., Thakur, A., Verma, R. K., Singh, C., Goyal, M., Kumar, J., & Namdeo, A. G. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04256-8 · Cited by 50
“Free radicals-induced damage, as identified in AD, comprises advanced glycation end products (AGEs), nitration, per-oxidation of lipids, carbonyl-related post-translational modifications of neurofilament protein, and free carbonyls [65–67].”
Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases
Wang, X., Wang, Z., Cao, J., Dong, Y., & Chen, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189902 · Cited by 43
“The expression of TFR1 in BV2 microglia cells in vitro and in microglia of C57BL/6 mice in vivo has been reported [84,86].”
BackgroundPhospholipid Membrane Transport and Associated Diseases
Ventura, R., Martínez-Ruíz, I., & Hernández‐Álvarez, M. I. (2022) · Biomedicines · doi:10.3390/biomedicines10051201 · Cited by 43
“These phospholipids have an important role in atherosclerosis pathogenesis [50,51].”
BackgroundSui, Z., Wei, C., Wang, X., Zhou, H., Liu, C., Mai, K., & He, G. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114672 · Cited by 42
Research progress on perioperative blood-brain barrier damage and its potential mechanism
Qiu, Y., Mo, C., Xu, S., Chen, L., Ye, W., Kang, Y., Chen, G., & Zhu, T. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1174043 · Cited by 45
“Targeted regulation of ferroptosis may improve brain homeostasis in patients with neurodegenerative diseases and ischemic stroke, thus affecting the prognosis (Millán et al., 2021; Park et al., 2021).”
BackgroundMelatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis
Zhang, F., Lin, B., Huang, S., Wu, P., Zhou, M., Zhao, J., Hei, X., Ke, Y., Zhang, Y., & Huang, D. (2023) · Antioxidants · doi:10.3390/antiox12061173 · Cited by 42
“Both MDA and 4–hydroxynonenal (4–HNE) are very common end products of lipid peroxidation and have been shown to be directly involved in inducing ferroptosis [27].”
BackgroundWu, Z., Bai, Y., Qi, Y., et al. (2023) · Pharmaceutical Biology · doi:10.1080/13880209.2023.2212700 · Cited by 42
“Regarding ferroptosis, NOX4 has been found to induce ferroptosis in astrocytes by impairing the mitochondrial metabolism and promoting the lipid peroxidation (Park et al. 2021).”
BackgroundGuo, J., Chen, L., & Ma, M. (2023) · Current Medicinal Chemistry · doi:10.2174/0929867330666230607125054 · Cited by 42
Cerasuolo, M., Meo, I. D., Auriemma, M. C., Trojsi, F., Maiorino, M. I., Cirillo, M., Esposito, F., Polito, R., Colangelo, A. M., Paolisso, G., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119637 · Cited by 47
“While some studies argue that ROS production is unnecessary for ferroptosis [43], more recent studies have confirmed the need and contribution of mitochondrial ROS production, associated with DNA stress and metabolic reprogramming, in promoting lipid peroxidation with consequent induction of ferroptosis [44,45].”
BackgroundPan, Y., Li, J., Lin, P., Wan, L., Qu, Y., Cao, L., & Wang, L. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1348410 · Cited by 49
Liu, P., Chen, W., Kang, Y., Wang, C., Wang, X., Liu, W., Hayashi, T., Qiu, Z., Mizuno, K., Hattori, S., et al. (2023) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2023.109691 · Cited by 44
Fu, X., Han, H., Yang, H., Xu, B., Dai, W., Liu, L., He, T., Du, X., & Pei, X. (2024) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2300138 · Cited by 45
“MDA is a major break‐ down product of lipid peroxidation reduced to fatty alcohol (LOOH) by GPX4 (Park et al., 2021); in add‑ ition, the intracellular Fe 2+ , MDA, GSH, and lipid perox‐ idation levels are regarded as ferroptosis biomarkers (Chen et al., 2021), which were also tested in our study.”
BackgroundSelf-citationWei, Y., Li, H., Li, Y., Zeng, Y., Quan, T., Leng, Y.-E., Chang, E., Bai, Y., Bian, Y., & Hou, Y. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1496661 · Cited by 43
Wei, Y., Zhu, Z., Hu, H., Guan, J., Yang, B., & Zhao, H. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174970 · Cited by 42
Li, M.-F., Wang, H., Lu, Y., & Cai, J. (2023) · Immunity, Inflammation and Disease · doi:10.1002/iid3.820 · Cited by 38
“NADPH oxidase 4 (NOX4) is not only a member of the NOXs enzyme family that produces ROS, but also a major source of ROS.10 Also, NOX4 has been proven to be involved in the occurrence and development of various diseases including COPD, where NOX4 expression is both upregulated in epithelial cells and small airway smoot…”
Background
Metadata
- Authors
- Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S.
- Affiliations
- Soonchunhyang University (KR)
- Soonchunhyang University Hospital Cheonan (KR)
- Corresponding author
- Yoo, Ik Dong
- Moon, Jong-Seok
- ORCID
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 41
- Pages
- 101947
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC8027773
- OpenAlex
- W3136661179
- Cited by
- 683
- References
- 92
- Citations by year
- 2026: 139 · 2025: 145 · 2024: 187 · 2023: 128 · 2022: 74 · 2021: 10
- FWCI
- 62.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Soonchunhyang University
- National Research Foundation of Korea
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX4, ferroptosis, astrocytes, Alzheimer's disease, oxidative stress, lipid peroxidation, mitochondrial dysfunction, mitochondrial respiration, mitochondrial electron transport chain, mitochondrial reactive oxygen species, mitochondrial fragmentation, 4-hydroxynonenal, malondialdehyde, APP/PS1 mice, reactive oxygen species
- MeSH terms
- NADPH Oxidase 4, Ferroptosis, Alzheimer Disease, Animals, Astrocytes, Humans, Mitochondria, Lipid Peroxidation, Reactive Oxygen Species, Oxidative Stress, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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