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Neuronal cell demise represents a prevalent occurrence throughout the advancement of Alzheimer's disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Its potential mechanisms include aggregation of soluble amyloid-beta (Aβ) to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFTs), neuroinflammation, ferroptosis, oxidative stress, liquid-liquid phase separation (LLPS) and metal ion disorders. Among them, ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. The sensitivity to ferroptosis is tightly linked to numerous biological processes. Moreover, emerging evidences indicate that LLPS has great impacts on regulating human health and diseases, especially AD. Soluble Aβ can undergo LLPS to form liquid-like droplets, which can lead to the formation of insoluble amyloid plaques. Meanwhile, tau has a high propensity to condensate via the mechanism of LLPS, which can lead to the formation of NFTs. In this review, we summarize the most recent advancements pertaining to LLPS and ferroptosis in AD. Our primary focus is on expounding the influence of Aβ, tau protein, iron ions, and lipid oxidation on the intricate mechanisms underlying ferroptosis and LLPS within the domain of AD pathology. Additionally, we delve into the intricate cross-interactions that occur between LLPS and ferroptosis in the context of AD. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for AD., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Obsessive-Compulsive Disorder (OCD) poses a multifaceted challenge in psychiatry, with various subtypes and severities greatly impacting well-being. Recent scientific attention has turned towards lipid metabolism, particularly the neurolipidome, in response to clinical demands for cost-effective diagnostics and therapies. This scoping review integrates recent animal, translational, and clinical studies to explore impaired neurolipid metabolism mechanisms in OCD's pathogenesis, aiming to enhance future diagnostics and therapeutics. Five key neurolipids - endocannabinoids, lipid peroxidation, phospholipids, cholesterol, and fatty acids - were identified as relevant. While the endocannabinoid system shows promise in animal models, its clinical application remains limited. Conversely, lipid peroxidation and disruptions in phospholipid metabolism exhibit significant impacts on OCD's pathophysiology based on robust clinical data. However, the role of cholesterol and fatty acids remains inconclusive. The review emphasises the importance of translational research in linking preclinical findings to real-world applications, highlighting the potential of the neurolipidome as a potential biomarker for OCD detection and monitoring. Further research is essential for advancing OCD understanding and treatment modalities., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Disruption of circadian rhythms contributes to deficits in cognitive functions during aging. Up to date, the biochemical, molecular and chronobiological bases of such deterioration have not been completely elucidated. Here, we aim: 1) to investigate the endogenous nature of 24 h-rhythms of antioxidant defenses, oxidative stress, clocḱ's, and neurotrophic factors expression, in the rat temporal cortex (TC), and 2) to study the consequences of aging on the circadian organization of those factors. We observed a circadian organization of antioxidant enzymes activity, lipoperoxidation and the clock, BMAL1 and RORa, proteins, in the TC of young rats. Such temporal organization suggests the existence of a two-way communication among clock transcription factors and antioxidant defenses. This might generate the rhythmic and circadian expression of Bdnf and Rc3 genes involved in the TC-depending cognitive function. Noteworthy, such circadian organization disappears in the TC of aged rats. Aging also reduces glutathione peroxidase activity and expression, and it increases lipid peroxidation, throughout a 24 h-period. An increased oxidative stress makes the cellular redox environment change into an oxidative status which alters the endogenous clock activity and disrupts the circadian organization of, at least part, of the molecular basis of the synaptic plasticity in the TC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Ferroptosis is a type of cell death that depends on iron and is driven by lipid peroxidation, playing a crucial role in neuronal death during stroke. A central element in this process is the inactivation of glutathione peroxidase 4 (GPx4), an antioxidant enzyme that helps maintain redox balance by reducing lipid hydroperoxides. This review examines the critical function of GPx4 in controlling neuronal ferroptosis following ischemic and hemorrhagic stroke. We explore the mechanisms through which GPx4 becomes inactivated in various stroke subtypes. In strokes, excess glutamate depletes glutathione (GSH) and products of hemoglobin breakdown overwhelm GPx4. Studies using genetic models with GPx4 deficiency underscore its vital role in maintaining neuronal survival and function. We also consider new therapeutic approaches to enhance GPx4 activity, including novel small molecule activators, adjustments in GSH metabolism, and selenium supplementation. Additionally, we outline the potential benefits of combining these GPx4-focused strategies with other anti-ferroptotic methods like iron chelation and lipoxygenase inhibition for enhanced neuroprotection. Furthermore, we highlight the significance of understanding the timing of GPx4 inactivation during stroke progression to design effective therapeutic interventions., Competing Interests: Declaration of Competing Interest The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Ferritinophagy is a regulatory pathway of iron homeostasis. It is a process in which nuclear receptor coactivator 4 (NCOA4) carries ferritin to autophagolysosomes for degradation. After ferritin is degraded by autophagy, iron ions are released, which promotes the labile iron pool (LIP) to drive the Fenton reaction to cause lipid peroxidation. Furthermore, ferroptosis promoted by the accumulation of lipid reactive oxygen species (ROS) induced by ferritinophagy can cause a variety of systemic diseases. In clinical studies, targeting the genes regulating ferritinophagy can prevent and treat such diseases. This article describes the key regulatory factors of ferritinophagy and the mechanism of ferritinophagy involved in ferroptosis. It also reviews the damage of ferritinophagy to the body, providing a theoretical basis for further finding clinical treatment methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Context Sires differ in their ability to produce viable blastocysts, yet our understanding of the cellular mechanisms regulated by the sire during early embryo development is limited. Aims The first aim was to characterise autophagy and reactive oxygen species (ROS) in embryos produced by high and low performing sires under normal and stress culture conditions. The second aim was to evaluate DNA damage and lipid peroxidation as mechanisms that may be impacted by increased cellular stress, specifically oxidative stress. Methods Embryos were produced using four high and four low performing sires based on their ability to produce embryos. Autophagy and ROS were measured throughout development. To evaluate oxidative stress response, autophagy, and ROS were measured in 2-6 cell embryos exposed to heat stress. To understand how cellular stress impacts development, DNA damage and lipid peroxidation were assessed. Key results Under normal conditions, embryos from low performing sires had increased ROS and autophagy. Under heat stress, embryos from low performing sires had increased ROS, yet those from high performing sires had increased autophagy. There was no difference in DNA damage or lipid peroxidation. Conclusions Results suggest that embryos from low performing sires may begin development under increased cellular stress, and autophagy potentially increases to mitigate the impacts of stress. Implications There is potential for improving embryonic competence through selection of sires with lower stress-related markers.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathogenesis, which involves the formation of amyloid plaques and neurofibrillary tangles. Many recent studies have revealed a close association between ferroptosis and the pathogenesis of AD. Factors such as ferroptosis-associated iron overload, lipid peroxidation, disturbances in redox homeostasis, and accumulation of reactive oxygen species have been found to contribute to the pathological progression of AD. In this review, we explore the mechanisms underlying ferroptosis, describe the link between ferroptosis and AD, and examine the reported efficacy of ferroptosis inhibitors in treating AD. Finally, we discuss the potential challenges to ferroptosis inhibitors use in the clinic, enabling their faster use in clinical treatment., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High-altitude environments present extreme conditions characterized by low barometric pressure and oxygen deficiency, which can disrupt brain functioning and cause edema formation. The objective of the present study is to investigate several biomolecule expressions and their role in the development of High Altitude Cerebral Edema in a rat model. Specifically, the study focuses on analyzing the changes in total arginase, nitric oxide, and lipid peroxidation (MDA) levels in the brain following acute hypobaric hypoxic exposure (7620 m, SO 2 =8.1 %, for 24 h) along with the histopathological assessment. The histological examination revealed increased TNF-α activity, and an elevated number of mast cells in the brain, mainly in the hippocampus and cerebral cortex. The research findings demonstrated that acute hypobaric hypoxic causes increased levels of apoptotic cells, shrinkage, and swelling of neurons, accompanied by the formation of protein aggregation in the brain parenchyma. Additionally, the level of nitric oxide and MDA was found to have increased (p<0.0001), however, the level of arginase decreased indicating active lipid peroxidation and redox imbalance in the brain. This study provides insights into the pathogenesis of HACE by evaluating some biomolecules that play a pivotal role in the inflammatory response and the redox landscape in the brain. The findings could have significant implications for understanding the neuronal dysfunction and the pathological mechanisms underlying HACE development., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental diseases. Epidemiological data report that males have been diagnosed with autism more frequently than females. However, recent studies hypothesize that females' low incidence might be underestimated due to standard clinical measures of ASD behavioural symptoms, mostly derived from males. Indeed, up to now, ASD mouse models focused mainly on males, considering the prevalence of the diagnosis in that sex. Regarding ASD aetiopathogenesis, it has been recently reported that oxidative stress might be implicated in its onset and development, suggesting an association with ASD typical repetitive behaviours that still need to be disentangled. Here, we investigated possible behavioural and molecular sex-related differences by using the BTBR mouse model of idiopathic ASD. To this aim, animals were exposed to behavioural tests related to different ASD core symptoms and comorbidities, i.e. stereotyped repertoire, social dysfunctions, hyperlocomotion and risk-taking behaviours. Moreover, we analyzed hippocampal levels of pro-oxidant and anti-oxidant enzymes, together with biomarkers of oxidative stress and lipid peroxidation. Our results showed that BTBR females did not display the same patterns for repetitive behaviours as the male counterpart. From a biomolecular point of view, we found an increase in oxidative stress and pro-oxidant enzymes, accompanied by deficient enzymatic anti-oxidant response, only in BTBR males compared to C57BL/6 male mice, while no differences were retrieved in females. Overall, our study suggests that in females there is an urgent need to depict the distinct ASD symptomatology, accompanied by the identification of sex-specific pharmacological targets., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context Preeclampsia is a common pregnancy complication, posing significant risks to both the mother and fetus. Predicting and determining the risks of this disease is crucial. Aims This research aims to understand the pathogenetic role of several factors in the development and progression of preeclampsia, particularly in relation to its severity in pregnant patients. Methods The study included 60 pregnant women diagnosed with either mild or severe preeclampsia and 40 healthy pregnant women for comparison. Blood plasma was analysed using biochemical methods, and blood microcirculation parameters were determined to identify homeostatic abnormalities in early preeclampsia. Key results A molecular genetic study revealed the frequency of the endothelial nitric oxide gene eNOSC774T . Homeostatic abnormalities were statistically correlated with polymorphic genotypes of the eNOSC774T gene. Conclusions The research found a correlation between the T774T eNOS genotype mutation and the severity of preeclampsia, alongside significant homeostasis abnormalities in patients. Implications The T774T mutant genotype of the eNOS gene and higher levels of lipid peroxidation products are strongly linked to the severity and progression of preeclampsia. This highlights a significant connection between genetic predisposition and biochemical abnormalities in the disease's development.

Cerebral ischemia-reperfusion injury (CIRI) is the second leading cause of death worldwide, posing a huge risk to human life and health. Therefore, investigating the pathogenesis underlying CIRI and developing effective treatments are essential. Ferroptosis is an iron-dependent mode of cell death, which is caused by disorders in iron metabolism and lipid peroxidation. Previous studies demonstrated that ferroptosis is also a form of autophagic cell death, and nuclear receptor coactivator 4(NCOA4) mediated ferritinophagy was found to regulate ferroptosis by interfering with iron metabolism. Ferritinophagy and ferroptosis are important pathogenic mechanisms in CIRI. This review mainly summarizes the link and regulation between ferritinophagy and ferroptosis and further discusses their mechanisms in CIRI. In addition, the potential treatment methods targeting ferritinophagy and ferroptosis for CIRI are presented, providing new ideas for the prevention and treatment of clinical CIRI in the future., (© 2024. The Author(s).)

Ferroptosis is a novel type of iron-dependent programmed cell death characterised by intracellular iron overload, increased lipid peroxidation and abnormal accumulation of reactive oxygen species.It has been implicated in the progression of several diseases including cancer, ischaemia-reperfusion injury, neurodegenerative diseases and liver disease. The etiology of endometriosis (EMS) is still unclear and is associated with multiple factors, often accompanied by various forms of cell death and a complex microenvironment. In recent decades, the role of non-traditional forms of cell death, represented by ferroptosis, in endometriosis has come to the attention of researchers. This article reviews the transitional role of iron homeostasis in the development of ferroptosis, the characteristics and regulatory mechanisms of ferroptosis, and focuses on summarising the links between iron death and various pathogenic mechanisms of EMS, including oxidative stress, dysregulation of lipid metabolism, inflammation, autophagy and epithelial-mesenchymal transition. The possible applications of ferroptosis in the treatment of EMS, future research directions and current issues are discussed with the aim of providing new ideas for further understanding of EMS., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Excessively high or synchronized neuronal activity in the brain is the underlying cause of epilepsy, a condition of the central nervous system. Epilepsy is caused mostly by an imbalance in the activity of inhibitory and excitatory neural networks. Recurrent or prolonged seizures lead to neuronal death, which in turn promotes epileptogenesis and epileptic seizures. Ferrous ion-mediated cell death is known as ferroptosis, which is due to the accumulation of lipid peroxidation products resulting from compromise of the glutathione (GSH)-dependent antioxidant system. The pathophysiology of epilepsy has been linked to anomalies in the glutathione peroxidase 4 (GPX4)/GSH redox pathway, lipid peroxidation, and iron metabolism. Studies have shown that inhibiting ferroptosis may alleviate cognitive impairment and decrease seizures, indicating that it is neuroprotective. With the hope of aiding the development of more novel approaches for the management of epilepsy, this research aimed to examine the role of ferroptosis in this disease., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

BACKGROUND Either a reduction in antioxidant levels or an accumulation of reactive oxygen species can heighten susceptibility to oxidative damage in disc cells. To date, no research has investigated the levels of lipid peroxidation products (thiobarbituric acid reactive substances [TBARs]), reduced glutathione (GSH), and glutathione peroxidase (GPx) in excised human lumbar disc tissues affected by degenerative disease. Therefore, this study aimed to evaluate lipid peroxidation products in excised disc tissues from patients with degenerative disc disease. MATERIAL AND METHODS Forty-two patients were enrolled. Patients were divided into lumbar disc degeneration (LDD) and nonlumbar disc degeneration (nonLDD) groups according to Pfirrmann classification. Intervertebral discs were obtained from all patients during the operation and were homogenized for analysis. TBARs levels were measured using fluorometry. GSH levels and GPx activity were quantified spectrophotometrically using a kinetic method. RESULTS TBARs levels in excised discs from LDD patients (5.18±4.14) were significantly higher than those from nonLDD patients (2.56±1.23, P=0.008). The levels of TBARs tended to increase with the severity of degeneration according to the Pfirrmann classification. However, these 2 groups showed no significant differences in reduced glutathione levels or glutathione peroxidase activity (P>0.05). Patients with LDD exhibited a worse health-related quality of life, reflected in lower utility and EQ-VAS scores and higher Oswestry disability index scores. CONCLUSIONS There was a notable increase in lipid peroxidation products in the excised intervertebral discs of patients with LDD. This finding suggests that oxidative stress may contribute to the development of disc degeneration.

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers., Competing Interests: Declaration of interests B.R.S. is an inventor on patents and patent applications involving small molecule drug discovery and ferroptosis; holds equity in Sonata Therapeutics; holds equity in and serves as a consultant to Exarta Therapeutics and ProJenX, Inc.; and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. X.J. is an inventor on patents related to autophagy and cell death and holds equity of and consults for Exarta Therapeutics and Lime Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ferroptosis, a regulated cell death hallmarked by unrestrained lipid peroxidation, plays a pivotal role in the pathophysiology of various diseases, making it a promising therapeutic target. Glutathione peroxidase 4 (GPX4) prevents ferroptosis by reducing (phospho)lipid hydroperoxides, yet evaluation of its actual activity has remained arduous. Here, we present a tangible method using affinity-purified GPX4 to capture a snapshot of its native activity. Next to measuring GPX4 activity, this improved method allows for the investigation of mutational GPX4 activity, exemplified by the GPX4 U46C mutant lacking selenocysteine at its active site, as well as the evaluation of GPX4 inhibitors, such as RSL3, as a showcase. Furthermore, we apply this method to the second ferroptosis guardian, ferroptosis suppressor protein 1, to validate the newly identified ferroptosis inhibitor WIN62577. Together, these methods open up opportunities for evaluating alternative ferroptosis suppression mechanisms., Competing Interests: Declaration of interests M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The interaction of iron and oxygen is an integral part of the development of life on Earth. Nonetheless, this unique chemistry continues to fascinate and puzzle, leading to new biological ventures. In 2012, a Columbia University group recognized this interaction as a central event leading to a new type of regulated cell death named "ferroptosis." The major feature of ferroptosis is the accumulation of lipid hydroperoxides due to (1) dysfunctional antioxidant defense and/or (2) overwhelming oxidative stress, which most frequently coincides with increased content of free labile iron in the cell. This is normally prevented by the canonical anti-ferroptotic axis comprising the cystine transporter xCT, glutathione (GSH), and GSH peroxidase 4 (GPx4). Since ferroptosis is not a programmed type of cell death, it does not involve signaling pathways characteristic of apoptosis. The most common way to prove this type of cell death is by using lipophilic antioxidants (vitamin E, ferrostatin-1, etc.) to prevent it. These molecules can approach and detoxify oxidative damage in the plasma membrane. Another important aspect in revealing the ferroptotic phenotype is detecting the preceding accumulation of lipid hydroperoxides, for which the specific dye BODIPY C11 is used. The present manuscript will show how ferroptosis can be induced in wild-type medulloblastoma cells by using different inducers: erastin, RSL3, and iron-donor. Similarly, the xCT-KO cells that grow in the presence of NAC, and which undergo ferroptosis once NAC is removed, will be used. The characteristic "bubbling" phenotype is visible under the light microscope within 12-16 h from the moment of ferroptosis triggering. Furthermore, BODIPY C11 staining followed by FACS analysis to show the accumulation of lipid hydroperoxides and consequent cell death using the PI staining method will be used. To prove the ferroptotic nature of cell death, ferrostatin-1 will be used as a specific ferroptosis-preventing agent.

Lipid peroxidation (LPO) is a complex process that, depending on the context, can either result in oxidative injury or promote redox homeostasis. LPO is a series of reactions in which polyunsaturated fatty acids are attacked by free radicals that result in the synthesis of lipid peroxides. LPO can alter membrane fluidity and operation and produce secondary products that amplify oxidative stress. LPO can activate cellular signaling pathways that promote antioxidant defense mechanisms that provide oxidative stress protection by elevating antioxidant enzyme action potentials. Enzymatic and nonenzymatic mechanisms tightly regulate LPO to prevent excessive LPO and its adverse consequences. This article emphasizes the dual nature of LPO as a mechanism that can both damage cells and regulate redox homeostasis. In addition, it also highlights the major enzymatic and nonenzymatic mechanisms that tightly regulate LPO to prevent excessive oxidative damage. More importantly, it emphasizes the importance of understanding the cellular and biochemical complexity of LPO for developing strategies targeting this process for efficient management of plant stress., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chetan Keswani reports financial support was provided by Ministry of Science and Higher Education of the Russian Federation., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The problem of chronic rhinitis (CR) remains unresolved in the world, while it has a negative impact on the quality of life of patients. Chronic forms of rhinitis suffer from 10-20% of the population, and its symptoms in epidemiological studies are noted in 40% of respondents. One of the leading mechanisms of disease occurrence is oxidative stress., Objective: To study the state of the processes of lipid peroxidation and antioxidant protection in various types of chronic rhinitis., Material and Methods: The study included 50 patients with CR, of which 21 were with chronic allergic rhinitis (CALR), 20 with chronic vasomotor rhinitis (CVR), 9 with chronic atrophic rhinitis (CAR). The control group was represented by 50 practically healthy volunteers with no otorhinolaryngological complaints. The indicators of the LPO-AOD system in erythrocytes were evaluated by spectrophotometric methods. Statistical data processing was carried out using the Statistica 7.0 software package (StatSoft, USA)., Results: In all patients with CR in the blood erythrocytes, an increase in the level of malondialdehyde (MDA), a decrease in the activity of superoxide dismutase (SOD), catalase (CAT) relative to the control group was found. With CAR, the most pronounced changes are determined, with CVR - minimal. In patients with CR, lipid peroxidation is activated, MDA increases by 1.29 times, by 1.37 times with CAR, and by 1.31 times with CALR relative to normal values. The activity of the antioxidant system decreases, which reflects the classical variant of inhibition of antioxidant enzymes: SOD is reduced by 1.08 times in CAR, by 1.07 times in CALR, and 1.04 times in CVR, CAT in CAR is reduced by 1.02 times; CALR by 1.02 times, with CVR by 1.01 times. The coefficient of oxidative stress with CVR is 1.36, with CAR is 1.5, with CALR is 1.42., Conclusion: In CR, the predominance of pro-oxidant processes over antioxidant ones is revealed, a slight oxidative stress is detected, probably due to the presence of hypoxia and intoxication syndrome. An in-depth study of lipid peroxidation processes and factors of the antioxidant defense system, depending on the CR phenotype, can be used to correct therapy and prevent exacerbations, as well as markers of progression and prognosis of chronic rhinitis.

Introduction: The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer's disease (AD) and identify potential novel targets for AD therapy., Method: Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aβ protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aβ25-35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells., Results: The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aβ and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells., Conclusions: LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells., (© 2024 S. Karger AG, Basel.)

Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at the individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided by adaptations in oxidative physiology at the macroevolutionary scale. However, this hypothesis remains unexplored. Here, we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species (681 individuals with blood glucose data and 1021 individuals with oxidative state data). We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no clear evidence for blood glucose concentration being correlated with either antioxidant or lipid damage levels at the macroevolutionary scale, as opposed to the hypothesis postulating that high blood glucose levels entail oxidative costs. The only exception was the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings support the hypothesis that birds evolved adaptations preventing the (glyc)oxidative costs of high blood glucose observed at the within-species level. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds and possibly the paradoxical combination of long lifespan and high blood glucose levels relative to mammals., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

As cancer cells develop resistance to apoptosis, non-apoptotic cell death modalities, such as ferroptosis, have emerged as promising strategies to combat therapy-resistant cancers. Cells that develop resistance to conventional therapies or metastatic cancer cells have been shown to have increased sensitivity to ferroptosis. Therefore, targeting the regulatory elements of ferroptosis in cancer could offer novel therapeutic opportunities. In this review, we first provide an overview of the known ferroptosis regulatory networks and discuss recent findings on how they contribute to cancer plasticity. We then expand into the critical role of selenium metabolism in regulating ferroptosis. Finally, we highlight specific cases where induction of ferroptosis could be used to sensitize cancer cells to this form of cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ferroptosis is the type of cell death arising from uncontrolled and excessive lipid peroxidation. NADPH is essential for ferroptosis regulation because it supplies reducing equivalents for antioxidant defense systems and contributes to the generation of reactive oxygen species. Moreover, NADPH level serves as a biomarker for predicting the sensitivity of cells to ferroptosis. The ubiquitin-proteasome system governs the stability of many ferroptosis effectors. Recent research has revealed MARCHF6, the endoplasmic reticulum ubiquitin ligase, as an unprecedented NADPH sensor in the ubiquitin system and a critical regulator of ferroptosis involved in tumorigenesis and fetal development. This review summarizes the current understanding of NADPH metabolism and the ubiquitin-proteasome system in regulating ferroptosis and highlights the emerging importance of MARCHF6 as a vital connector between NADPH metabolism and ferroptosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Regulation of cell mortality for disease treatment has been the focus of research. Ferroptosis is an iron-dependent regulated cell death whose mechanism has been extensively studied since its discovery. A large number of studies have shown that regulation of ferroptosis brings new strategies for the treatment of various benign and malignant diseases. Iron excess and lipid peroxidation are its primary metabolic features. Therefore, genes involved in iron metabolism and lipid metabolism can regulate iron overload and lipid peroxidation through direct or indirect pathways, thereby regulating ferroptosis. In addition, glutathione (GSH) is the body's primary non-enzymatic antioxidants and plays a pivotal role in the struggle against lipid peroxidation. GSH functions as an auxiliary substance for glutathione peroxidase 4 (GPX4) to convert toxic lipid peroxides to their corresponding alcohols. Here, we reviewed the researches on the mechanism of ferroptosis in recent years, and comprehensively analyzed the mechanism and regulatory process of ferroptosis from iron metabolism and lipid metabolism, and then described in detail the metabolism of GPX4 and the main non-enzymatic antioxidant GSH in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Liu, Wang, Guo, Wang, Luo, Huang and Li.)

Ferroptosis is a non-apoptotic cell death regulated by iron-dependent lipid peroxidation. Glutathione (GSH), a key antioxidant against oxidative damage, is involved in one of the most important metabolic pathways of ferroptosis. Herein, an excellent plasmonic nanoprobe was developed for highly sensitive, in situ, dynamic real-time monitoring of intracellular GSH levels during ferroptosis. A nanoprobe was prepared by functionalizing gold nanoparticles (AuNPs) with the probe molecule crystal violet (CV). The fluctuation in the SERS signal intensity of CV via the competitive displacement reaction can be used to detect GSH. The advantages of the plasmonic nanoprobe including low-cost production techniques, outstanding stability and biocompatibility, high specificity and sensitivity towards GSH with a detection limit of 0.05 μM. It enables real-time dynamic monitoring of GSH levels in living cells during erastin-induced ferroptosis. This approach is expected to provide important theoretical support for elucidating the GSH-related ferroptosis metabolic mechanism and advancing our understanding of ferroptosis-based cancer therapy. Overview of the workflow of sensing principle for highly sensitive, in situ and dynamic tracking of intracellular GSH levels during drug-triggered ferroptosis process., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: We hypothesized that transcriptomic profiling of muscle satellite cells in peripheral artery disease (PAD) would identify damage-related pathways contributing to skeletal muscle myopathy. We identified a potential role for ferroptosis-a form of programmed lytic cell death by iron-mediated lipid peroxidation-as one such pathway. Ferroptosis promotes myopathy in ischemic cardiac muscle but has an unknown role in PAD., Methods: Muscle satellite cells from donors with PAD were obtained during surgery. cDNA libraries were processed for single-cell RNA sequencing using the 10X Genomics platform. Protein expression was confirmed based on pathways inferred by transcriptomic analysis., Results: Unsupervised cluster analysis of over 25 000 cells aggregated from 8 donor samples yielded distinct cell populations grouped by a shared unique transcriptional fingerprint. Quiescent cells were diminished in ischemic muscle while myofibroblasts and apoptotic cells were prominent. Differential gene expression demonstrated a surprising increase in genes associated with iron transport and oxidative stress and a decrease in GPX4 (glutathione peroxidase 4) in ischemic PAD-derived cells. Release of the danger signal HMGB1 (high mobility group box-1) correlated with ferroptotic markers including surface transferrin receptor and were higher in ischemia. Furthermore, lipid peroxidation in muscle satellite cells was modulated by ferrostatin, a ferroptosis inhibitor. Histology confirmed iron deposition and lipofuscin, an inducer of ferroptosis in PAD-affected muscle., Conclusions: This report presents a novel finding that genes known to be involved in ferroptosis are differentially expressed in human skeletal muscle affected by PAD. Targeting ferroptosis may be a novel therapeutic strategy to reduce PAD myopathy., Competing Interests: Disclosures None.

Background: Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses., Objectives: To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD., Methods: Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed., Results: The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027)., Conclusion: In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,β-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.

Accumulation of autofluorescent waste products, amyloids, and products of lipid peroxidation (LPO) are important hallmarks of aging. Until now, these processes have not been documented in Daphnia, a convenient model organism for longevity and senescence studies. We conducted a longitudinal cohort study of autofluorescence and Congo Red (CR) fluorescent staining for amyloids in four clones of D. magna. Additionally, we used a single time point cross-sectional common garden experiment within a single clone in which autofluorescence and BODIPY C11 fluorescence were measured. We observed a robust increase in autofluorescent spots that show diagnostic co-staining by Sudan Black indicating lipofuscin aggregates, particularly in the upper body region. There was also a significant clone-by-age interaction indicating that some genotypes accumulated lipofuscins faster than others. Contrary to predictions, CR fluorescence and lipid peroxidation did not consistently increase with age. CR fluorescence demonstrated a slight non-monotonous relationship with age, achieving the highest values at intermediate ages, possibly due to elimination of physiological heterogeneity in our genetically uniform cohorts. LPO demonstrated a significant ovary status-by-age interaction, decreasing with age when measured in Daphnia with full ovaries (late phase ovarian cycle) and showing no significant trend or slight increase with age when measured during the early phase in the ovarian cycle., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Ferroptosis is a pervasive non-apoptotic mode of cell death that is different from autophagy or necrosis. It is mainly caused by an imbalance between the production and degradation of lipid reactive oxygen species in cells. Several metabolic pathways and biochemical processes, such as amino acid and lipid metabolism, iron handling, and mitochondrial respiration, affect and regulate cell sensitivity to peroxidation and ferroptosis. Organ fibrosis, a pathological manifestation of several etiological conditions, leads to chronic tissue injury and is characterized by excessive deposition of extracellular matrix components. Excessive tissue fibrosis can have diverse pathophysiological effects on several organ systems, eventually causing organ dysfunction and failure. The current manuscript provides a review that illustrates the link between ferroptosis and organ fibrosis and to better understand the underlying mechanisms. It provides novel potential therapeutic approaches and targets for fibrosis diseases., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Vitamin A (retinol) is a lipid-soluble vitamin that acts as a precursor for several bioactive compounds, such as retinaldehyde (retinal) and isomers of retinoic acid. Retinol and all-trans-retinoic acid (atRA) penetrate the blood-brain barrier and are reported to be neuroprotective in several animal models. We characterised the impact of retinol and its metabolites, all-trans-retinal (atRAL) and atRA, on ferroptosis-a programmed cell death caused by iron-dependent phospholipid peroxidation. Ferroptosis was induced by erastin, buthionine sulfoximine or RSL3 in neuronal and non-neuronal cell lines. We found that retinol, atRAL and atRA inhibited ferroptosis with a potency superior to α-tocopherol, the canonical anti-ferroptotic vitamin. In contrast, we found that antagonism of endogenous retinol with anhydroretinol sensitises ferroptosis induced in neuronal and non-neuronal cell lines. Retinol and its metabolites atRAL and atRA directly interdict lipid radicals in ferroptosis since these compounds displayed radical trapping properties in a cell-free assay. Vitamin A, therefore, complements other anti-ferroptotic vitamins, E and K; metabolites of vitamin A, or agents that alter their levels, may be potential therapeutics for diseases where ferroptosis is implicated., Competing Interests: Declaration of Competing Interest AIB owns equity in Alterity Ltd, Cogstate Ltd, and a profit share in Collaborative Medicinal Development LLC., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure-activity-distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Ferroptosis is a mechanism of regulated necrotic cell death characterized by iron-dependent, lipid peroxidation-driven membrane destruction that can be inhibited by glutathione peroxidase 4. Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is triggered in cells with dysregulated iron and thiol redox metabolism, whereby the initial robust but selective accumulation of hydroperoxy polyunsaturated fatty acid-containing phospholipids is further propagated through enzymatic and non-enzymatic secondary mechanisms, leading to formation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the convergence of iron, thiol and lipid metabolic pathways. The kidney is particularly susceptible to redox imbalance. A growing body of evidence has linked ferroptosis to acute kidney injury in the context of diverse stimuli, such as ischaemia-reperfusion, sepsis or toxins, and to chronic kidney disease, suggesting that ferroptosis may represent a novel therapeutic target for kidney disease. However, further work is needed to address gaps in our understanding of the triggers, execution and spreading mechanisms of ferroptosis., (© 2023. Springer Nature Limited.)

Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.

The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, which are antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential, and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to the gain of cellular Na + and Ca 2+ concomitant with loss of K + . These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na + /K + -ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Altogether, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels, and the Na + /K + -ATPase as targets/effectors of this type of cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferroptosis in ALS remains unclear. In this research, bioinformatics analysis revealed a high correlation between ALS, ferroptosis, and Speedy/RINGO cell cycle regulator family member A (SPY1). Lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was generated by TFR1-imported excess free iron, decreased GSH, mitochondrial membrane dysfunction, upregulated ALOX15, and inactivation of GCH1, GPX4. SPY1 is a "cyclin-like" protein that has been proved to enhance the viability of hSOD1 G93A cells by inhibiting DNA damage. In our study, the decreased expression of SPY1 in ALS was resulted from unprecedented ubiquitination degradation mediated by MDM2 (a nuclear-localized E3 ubiquitin ligase). Further, SPY1 was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated GCH1/BH4 axis (a resistance axis of ferroptosis) and transferrin receptor protein 1 (TFR1)-induced iron. Additionally, neuron-specific overexpression of SPY1 significantly delayed the occurrence and prolonged the survival in ALS transgenic mice through the above two pathways. These results suggest that SPY1 is a novel target for both ferroptosis and ALS., (© 2022. The Author(s).)

Regulating non-apoptotic cell death of cancer cells provides a promising strategy to overcome apoptosis resistance during cancer treatment. Lipids are essential components to exacerbate several non-apoptotic cell death pathways. In the present study, unsaturated fatty acid (UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic acid have the potential to affect lipid metabolism. Notably, UFA liposomes markedly increased cellular reactive oxygen species (ROS) and down-regulated the expression of glutathione peroxidase 4 (GPX4) in tumor cells, resulting in lipid peroxidation, which in turn caused rapid membrane rupture and induced non-apoptotic cell death of tumor cells. Concomitantly, UFA liposomes induced ROS-mediated tumor-associated macrophages toward a tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment. Consequently, UFA liposomes substantially inhibited tumor growth in a melanoma model by promoting lipid peroxidation, inducing non-apoptotic cell death of tumor cells, and increasing infiltration of anti-tumor immune cells at tumor sites. Therefore, UFA liposomes regulate GXP4 to exacerbate lipid peroxidation and provide a versatile liposome platform for enhancing anti-tumor therapy which could be readily extended to the delivery of anticancer agents.

Ferroptosis is a form of regulated cell death that relies on iron and is characterized by the accumulation of lipid peroxides, resulting in oncotic cell swelling and eventual disruption of cellular membranes. Lipid peroxidation, a hallmark of ferroptosis, refers to the oxidative deterioration of lipids that contain carbon-carbon double bonds, particularly polyunsaturated fatty acids (PUFAs). Understanding the molecular mechanisms underlying the interplay between ferroptosis and lipid peroxidation and identifying reliable techniques for assessing lipid peroxidation levels are crucial for further advancements in this field of research. Various methods have been developed to detect lipid peroxidation levels, including C11-BODIPY (BODIPY™ 581/591 C11), liperfluo, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), Click-iT LAA (linoleamide alkyne), and liquid chromatography-mass spectrometry (LC-MS)-based epilipidomics (redox lipidomics). Currently, one of the most commonly used and effective methods is the C11-BODIPY assay, which utilizes a fluorescent probe that selectively sensitizes lipid peroxidation in cell membranes. Incorporating advanced techniques such as flow cytometry and fluorescence microscopy with C11-BODIPY dye is essential for accurate assessment of lipid peroxidation levels in ferroptosis. This chapter aims to provide comprehensive experimental protocols for detecting lipid peroxidation levels indicative of ferroptosis using C11-BODIPY staining and subsequent detection via flow cytometry and fluorescence microscopy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Ferroptosis is a regulated form of non-apoptotic cell death driven by iron-dependent lipid peroxidation. In the past decade, ferroptosis has been reported to be involved in the pathological role in the central nervous system degenerative diseases (e.g., Alzheimer's disease, Huntington's disease, and Parkinson's disease), stroke, traumatic brain injury, and brain tumor. However, how to reliably detect and classify ferroptosis from other cell death in pathological conditions remains a great challenge, especially in primary brain cells and brain tissues. Here, we summarize the methods and protocols (such as real-time PCR, western blotting, immunofluorescence staining, lipid peroxidation assay kits and probe, immunofluorescence staining, GPX activity and glutathione depletion assay kits, iron detection, and TEM) used in the present study to detect and classify ferroptosis in the brain., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of the study was to evaluate the state of oxidation processes and morphological changes in the heart of castrated rats during the development of epinephrine heart damage (EHD)., Patients and Methods: Materials and methods. The study was performed on 120 white male Wistar rats. The animals were divided into four series: 1 - control, 2 - castration. For EHD, rats were injected once intraperitoneally with a 0.18% solution of adrenaline hydrotartrate at the rate of 0.5 mg/kg of weight. Castration was performed under anesthesia. The concentration of diene and triene conjugates (DC, TC), Schiff's bases (SB), TBA-active products (TBA-ap), oxidatively modi"ed proteins (OMP), activity of superoxide dismutase (SOD) and catalase (CAT) were determined in the heart. A morphological study of preparations stained with Azantrichrome was carried out. All studies were performed in control, 1, 3, 7, 14 and 28 days after adrenaline injection., Results: Results: In the I series DC and TC increased after 1 day of EHD, fell to control values after 3 days, and then had wave-like character (highest - after 14 days). SB decreased (minimal after 7 days), TBA-ap increase (maximal after 14 days). OMP370 increased after 1 and 3 days, after 7 days they did not differ from the control, after 14 days they were higher than in control, and after 28 days they decreased to the control values. OMP430 and OMP530were greater than the control indicators in all terms, except the last; the maximum was noted after 14 days. The activity of antioxidant enzymes was lower than the control indicators at all times of the study. Castration caused an increase of lipid peroxidation. After 7 days, DC and TC, were lower and SB - higher, than in the I series. Castration caused a decrease in OMP. In EHD all values of OMP, compared to the castrated control rats, were higher at all studed times Castration leads to increase of SOD, and decrase of CAT. All indicators of SOD and CAT exceeded the indicators of animals of the I series at all times of the study. Biochemical changes are consistent with morphological changes. After injection of epinephrine, severe vascular disorders, adventitia edema, perivasal edema, endothelial cell damage, dilatation of hemicapillaries, full blood vessels, stasis, hemorrhages in the surrounding tissues, and sclerosing of the walls of arteries and venules were observed. Cardiomyocytes were swollen, shortening, necrosis was observed, myocytolysis was noted. Edema of the stroma was noted. In the stroma, around the vessels, located cells of connective tissue elements were observed. Indicate more damage to the myocardium in the process of development of EHD in animals of the I series., Conclusion: Conclusions: Castration of rats causes an increase of lipid peroxidation products and CAT activity in the heart, but a decrease in the content of OMP. Adrenaline injection causes activation of lipid peroxidation and an increase in the content of OMP. During the development of EHD, the activity of antioxidants is significantly higher in II group. Biochemical changes are consistent with morphological, and indicate more damage to the myocardium in the development of EHD in animals of the I series.

Ferroptosis is emerging as a promising strategy for suppressing multiple types of human cancers. Rapid and accurate assessment of the relative sensitivity to ferroptosis in biological samples will accelerate the development of ferroptosis-targeted therapies. We previously demonstrated that photochemical activation of membrane lipid peroxidation (PALP) that uses high-power lasers to induce localized polyunsaturated fatty acyl (PUFA)-lipid peroxidation can efficiently report ferroptosis sensitivity in live cells and tissues in situ. Here, we describe the experimental details for PALP analysis, including preparation of tissue sections, preparation of fluorescent lipid peroxidation reporter, sample staining, lipid peroxidation induced by laser source, and data processing. We envision predicting the relative sensitivity to ferroptosis of cellular and tissue samples is potentially useful for basic research and clinical investigations., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is a common and serious nervous system disease caused by the rupture or blockage of the cardiovascular system. It causes millions of deaths and disabilities every year, which is a huge burden on humanity. It may be induced by thrombosis, hypertension, hyperlipidemia, hyperglycemia, smoking, advanced age and so on. According to different causes, stroke can be generally divided into hemorrhagic stroke and ischemic stroke, whose pathogenesis and treatment are quite different. Ferroptosis is a new type of cell death first defined in 2012, which is characterized by non-apoptotic, iron-dependent, and over-accumulated lipid peroxides. Excess lipid reactive oxygen species produced during ferroptosis eventually leads to oxidative cell death. Ferroptosis has been shown to occur and play an important role in tumors, neurological diseases, kidney injury, and ischemia-reperfusion injury. Ferroptosis is also closely related to the pathogenesis of stroke. Moreover, scientists have successfully intervened in the process of stroke in animal models by regulating ferroptosis, indicating that ferroptosis is a new potential target for the treatment of stroke. This paper systematically summarizes the involvement and role of ferroptosis in the pathogenesis of stroke and predicts the potential of ferroptosis in the treatment of stroke. Ferroptosis in stroke. Stroke induces iron overload and lipid metabolism disorders. Elevated iron catalyzes lipid peroxidation and eventually triggers ferroptosis. Conversely, the GSH/GPX4 pathway, as well as CoQ10, Fer-1, and Lip-1, inhibits lipid peroxidation and, thus, alleviates ferroptosis. GSH glutathione; GPX4 glutathione peroxidase 4; CoQ10 coenzyme Q10; Lip-1 liproxstatin-1; Fer-1 ferostatin-1., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the x c - GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system x c - , composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage.

Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance., (© 2022. The Author(s).)

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation and has been implicated in multiple pathological conditions. Glutathione peroxidase 4 (GPX4) plays an essential role in inhibiting ferroptosis by eliminating lipid peroxide using glutathione (GSH) as a reductant. In this study, we found Ellman's reagent DTNB and a series of disulfide compounds, including disulfiram (DSF), an FDA-approved drug, which protect cells from erastin-induced ferroptosis. Mechanistically, DTNB or DSF is conjugated to multiple cysteine residues in GPX4 and disrupts GPX4 interaction with HSC70, an adaptor protein for chaperone mediated autophagy, thus preventing GPX4 degradation induced by erastin. In addition, DSF ameliorates concanavalin A induced acute liver injury by suppressing ferroptosis in a mouse model. Our work reveals a novel regulatory mechanism for GPX4 protein stability control. We also discover disulfide compounds as a new class of ferroptosis inhibitors and suggest therapeutic repurposing of DSF in treating ferroptosis-related diseases.

Reactive oxygen species (ROS), a by-product of aerobic life, are highly reactive molecules with unpaired electrons. The excess of ROS leads to oxidative stress, instigating the peroxidation of polyunsaturated fatty acids (PUFA) in the lipid membrane through a free radical chain reaction and the formation of the most bioactive aldehyde, known as 4-hydroxynonenal (4-HNE). 4-HNE functions as a signaling molecule and toxic product and acts mainly by forming covalent adducts with nucleophilic functional groups in proteins, nucleic acids, and lipids. The mitochondria have been implicated as a site for 4-HNE generation and adduction. Several studies clarified how 4-HNE affects the mitochondria's functions, including bioenergetics, calcium homeostasis, and mitochondrial dynamics. Our research group has shown that 4-HNE activates mitochondria apoptosis-inducing factor (AIFM2) translocation and facilitates apoptosis in mice and human heart tissue during anti-cancer treatment. Recently, we demonstrated that a deficiency of SOD 2 in the conditional-specific cardiac knockout mouse increases ROS, and subsequent production of 4-HNE inside mitochondria leads to the adduction of several mitochondrial respiratory chain complex proteins. Moreover, we highlighted the physiological functions of HNE and discussed their relevance in human pathophysiology and current discoveries concerning 4-HNE effects on mitochondria.

Periodontitis is a chronic inflammatory disease associated with bacterial biofilm. It is characterized by loss of periodontal support tissue and has long been considered as a "silent disease". Because it is difficult to prevent and has a health impact that can not be ignored, researchers have been focusing on a mechanism-based treatment model. Ferroptosis is an iron-dependent regulatory form of cell death, that directly or indirectly affects glutathione peroxidase through different signaling pathways, resulting in a decrease in cell antioxidant capacity, accumulation of reactive oxygen species and lipid peroxidation, which cause oxidative cell death and tissue damage. Recently, some studies have proven that iron overload, oxidative stress, and lipid peroxidation exist in the process of periodontitis. Based on this, this article reviews the relationship between periodontitis and ferroptosis, in order to provide a theoretical reference for future research on the prevention and treatment of periodontal disease.

The indicators of spermatogenesis and the state of LPO and antioxidant protection in men with pathozoospermia after COVID-19 were assessed before and after treatment an antioxidant complex. Blood plasma served as the material for biochemical studies. In the examined patients, the parameters of spermatogenesis, as well as blood concentration of LPO components (diene conjugates and TBA-reactive substances) were analyzed. The total antioxidant activity of the blood was determined as an indicator characterizing the total activity of LPO inhibitors and determining its buffer capacity. In patients recovered from COVID-19, an increase in spermatogenesis disorders and shifts towards the predominance of prooxidant factors were observed. After a course (1 month) of antioxidant complex, patients showed increased sperm motility, decreased leukocyte count in the ejaculate, and restored balance in the prooxidant-antioxidant system towards antioxidant components. The effectiveness of correction of post-COVID disorders largely depends on the degree of damage to the structure and function of cell membranes caused by oxidative stress. The use of the antioxidant complex is a promising option, because it reduces the level of LPO, enhances antioxidant protection of the body, and also normalizes some parameters of spermatogenesis., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Oxidative stress can promote the oxidation of lipoproteins and polyunsaturated fatty acids present in cell membranes; an event known as lipid peroxidation (LPO). LPO has been associated with carcinogenesis and cancer progression, however, its meaning concerning the clinicopathological aspects of human breast cancer is not clear. This study investigated LPO profiles in tumor and plasma samples from breast cancer patients (n = 140) considering their clinicopathological features (age at diagnosis, menopausal status, body mass index, tumor histological grade, tumor size, ki-67 proliferation index, presence of metastasis, chemotherapy response, the molecular subtype of cancer and overall survival status). LPO levels were estimated by tert-butyl hydroperoxide-initiated chemiluminescence. High LPO levels were found regarding poor prognosis parameters as young age at diagnosis (p = 0.006 in tissue), premenopausal patients (p = 0.012 in tissue), high-grade tumors (p = 0.010 in tissue and p = 0.002 in plasma), metastatic disease (p = 0.046 in tissue), chemoresistant tumors (p = 0.041 in tissue), disease relapse (p = 0.018 in tissue and p = 0.009 in plasma) and overall survival status (p = 0.001 in plasma). Our findings point out the clinical meaning of LPO and highlight it as an oxidative stress event linked to poor prognosis and disease aggressiveness in breast cancer patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6 -/- mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)