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Special Issue "Ferroptosis and Its Potential Role in the Physiopathology of Brain Injury"

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 7007

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Dr. Chengliang Luo

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Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
Interests: brain injury; traumatic brain injury; cognitive function; ferroptosis; cell death; mitochondrion; oxidative stress; neuroinflammation; forensic pathology

Special Issue Information

Dear Colleagues,

As a novel mode of regulated cell death, ferroptosis has distinctive morphological and biochemical features, including morphological changes in mitochondria, the accumulation of iron, and lipid reactive oxygen species (ROS). Studies at present have shown that disturbances to iron homeostasis, lipid ROS accumulation, and other manifestations related to ferroptosis can be detected in brain injury, suggesting that ferroptosis may play an important role in the physiopathology of brain injury, such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), ischemia/reperfusion injury, and hypoxic–ischemic injury.

We invite you to submit your latest original research findings or a review article to this Special Issue, which will bring together current research concerning the molecular mechanisms and potential roles of ferroptosis in the physiopathology of brain injury. This research can include both in vitro and in vivo studies relating to, but not limited to, any of the following topics: activation/inhibition mechanism of molecular mediators of ferroptosis after brain injury; modulation of signaling pathways of ferroptosis in brain injury; the relationship between ferroptosis and other mechanisms such as neuroinflammation and autophagy after brain injury; modulation of ferroptosis molecular mediators of brain injury; and the potential roles of ferroptosis in cognitive dysfunction caused by brain injury.

We look forward to your contribution.

Dr. Chengliang Luo
Guest Editor

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Keywords

ferroptosis
brain injury
cell death
lipid peroxidation
iron homeostasis

Published Papers (4 papers)

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Research

Open AccessArticle

Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice

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Antioxidants 2023, 12(3), 731; https://doi.org/10.3390/antiox12030731 - 16 Mar 2023

Cited by 7 | Viewed by 1354

Abstract

Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2^−/−) mice, more sever ferroptosis and neurological deficits were detected. Dimethyl fumarate (DMF)-mediated NRF2 activation alleviated neural dysfunction in TBI mice, partly due to TBI-induced ferroptosis mitigation. Additionally, FTH-FTL and FSP1 protein levels, associated with iron metabolism and the ferroptotic redox balance, were highly NRF2-dependent post-TBI. Thus, NRF2 is neuroprotective against TBI-induced ferroptosis through both the xCT-GPX4- and FTH-FTL-determined free iron level and the FSP1-regulated redox status. This yields insights into the neuroprotective role of NRF2 in TBI-induced neuronal damage and its potential use in TBI treatment. Full article

(This article belongs to the Special Issue Ferroptosis and Its Potential Role in the Physiopathology of Brain Injury)

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Open AccessCommunication

Increased Levels of Circulating Iron-Albumin Complexes in Peripheral Arterial Disease Patients

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Antioxidants 2023, 12(2), 503; https://doi.org/10.3390/antiox12020503 - 16 Feb 2023

Viewed by 753

Abstract

Under physiological conditions, extracellular iron circulates in the blood bound to transferrin. As a consequence of several pathologies, the circulating level of a Non-Transferrin Bound pool of Iron (NTBI) increases. The NTBI pool is biologically heterogeneous and represented by iron chelated either by small metabolites (citrate, amino acids, or cofactors) or by serum proteins. By promoting reactive oxygen species (ROS) and reactive nitrogen species (RNS) formation, NTBI causes oxidative stress and alteration of membrane lipids, seriously compromising the healthy state of organs and tissues. While NTBI involvement in several pathologies has been clarified, its contribution to vascular diseases remains to be investigated. Here we measure and analyze the pool of NTBI in the serum of a small group of peripheral arterial disease (PAD) patients. We show that: (i) the NTBI pool shifts from low molecular complexes to high-molecular ones in PAD patients compared to healthy controls; (ii) most of this NTBI is bound to the serum protein Albumin; (iii) this NTBI-Albumin complex can be isolated and quantitated following a simple immunoisolation procedure amenable to automation and suitable for clinical screening purposes. Full article

(This article belongs to the Special Issue Ferroptosis and Its Potential Role in the Physiopathology of Brain Injury)

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Open AccessArticle

Identification of Lipocalin 2 as a Ferroptosis-Related Key Gene Associated with Hypoxic-Ischemic Brain Damage via STAT3/NF-κB Signaling Pathway

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Antioxidants 2023, 12(1), 186; https://doi.org/10.3390/antiox12010186 - 12 Jan 2023

Cited by 3 | Viewed by 1849

Abstract

Hypoxic-ischemic brain damage (HIBD) is a common cause of death or mental retardation in newborns. Ferroptosis is a novel form of iron-dependent cell death driven by lipid peroxidation, and recent studies have confirmed that ferroptosis plays an important role in the development of HIBD. However, HIBD ferroptosis-related biomarkers remain to be discovered. An artificial neural network (ANN) was established base on differentially expressed genes (DEGs) related to HIBD and ferroptosis and validated by external dataset. The protein–protein interaction (PPI) network, support vector machine-recursive feature elimination (SVM-RFE) algorithms, and random forest (RF) algorithm were utilized to identify core genes of HIBD. An in vitro model of glutamate-stimulated HT22 cell HIBD was constructed, and glutamate-induced ferroptosis and mitochondrial structure and function in HT22 cells were examined by propidium iodide (PI) staining, flow cytometry, Fe²⁺ assay, Western blot, JC-1 kit, and transmission electron microscopy (TEM). In addition, Western blot and immunofluorescence assays were used to detect the NF-κB/STAT3 pathway. An HIBD classification model was constructed and presented excellent performance. The PPI network and two machine learning algorithms indicated two hub genes in HIBD. Lipocalin 2 (LCN2) was the core gene correlated with the risk of HIBD according to the results of differential expression analysis and logistic regression diagnostics. Subsequently, we verified in an in vitro model that LCN2 is highly expressed in glutamate-induced ferroptosis in HT22 cells. More importantly, LCN2 silencing significantly inhibited glutamate-stimulated ferroptosis in HT22 cells. We also found that glutamate-stimulated HT22 cells produced mitochondrial dysfunction. Furthermore, in vitro experiments confirmed that NF-κB and STAT3 were activated and that silencing LCN2 could have the effect of inhibiting their activation. In short, our findings reveal a molecular mechanism by which LCN2 may promote ferroptosis in HIBD through activation of the NF-κB/STAT3 pathway, providing new and unique insights into LCN2 as a biomarker for HIBD and suggesting new preventive and therapeutic strategies for HIBD. Full article

(This article belongs to the Special Issue Ferroptosis and Its Potential Role in the Physiopathology of Brain Injury)

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Open AccessArticle

D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

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Antioxidants 2022, 11(8), 1602; https://doi.org/10.3390/antiox11081602 - 19 Aug 2022

Cited by 4 | Viewed by 2190

Abstract

Repetitive seizures, a common phenomenon in diverse neurologic conditions such as epilepsy, can undoubtedly cause neuronal injury and our prior work reveals that ferroptosis is a contributing factor of neuronal damage post seizure. However, there is no drug available in clinical practice for ameliorating seizure-induced neuronal impairment via targeting ferroptosis. Our present work aimed to explore whether D-penicillamine (DPA), an originally approved drug for treating Wilson’s disease, inhibited neuronal ferroptosis and alleviated seizure-associated brain damage. Our findings revealed that DPA remarkably improved neuronal survival in kainic acid (KA)-treated mouse model. Furthermore, ferroptosis-associated indices including acyl-coA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (Ptgs2) gene and lipid peroxide (LPO) level were significantly decreased in KA mouse model after DPA treatment. In a ferroptotic cell death model induced by glutamate or erastin, DPA was also validated to evidently suppress neuronal ferroptosis. The results from RNA-seq analysis indicated that Aqp11, a gene coding previously reported channel protein responsible for transporting water and small solutes, was identified as a molecular target by which DPA exerted anti-ferroptotic potential in neurons. The experimental results from in vivo Aqp11 siRNA transfer into the brain also confirmed that knockdown of Aqp11 abrogated the inhibitory effect of seizure-induced ferroptosis after DPA treatment, suggesting that the effects of DPA on ferroptosis process are dependent upon Aqp11. In conclusion, DPA can be repurposed to cure seizure disorders such as epilepsy. Full article

(This article belongs to the Special Issue Ferroptosis and Its Potential Role in the Physiopathology of Brain Injury)

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