Advancing glioblastoma treatment through iron metabolism: A focus on TfR1 and Ferroptosis innovations.

Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach.

Protective function of albiflorin against ferroptosis in exhaustive exerciseinduced myocardial injury via the AKT/Nrf2/HO-1 signaling.

PURPOSE: It has been reported that exhaustive exercise (EE) causes myocyte injury, and eventually damages the function of the myocardia. Albiflorin (AF) has anti-inflammatory, antioxidant, and anti-apoptosis effects. In this study, we determined whether AF could mitigate the EE-induced myocardial injury and research the potential mechanisms. METHODS: The rat model of EE was built by forced treadmill running method. Rats were intraperitoneally injected with AF before EE once daily for one week. The relative factors levels were examined by commercial kits. The apoptosis was appraised using a TdT-mediated dUTP nick end labeling assay kit. The ACSL4, GPX4, Nrf2, pAKT/AKT, and HO-1 contents were assessed by western blot. RESULTS: AF lessened EE-induced cardiac myocytes ischemic/hypoxic injury and reduced the contents of myocardial injury biomarkers in the serum. AF lessened EE-induced cardiac myocyte apoptosis, inflammatory response, oxidative stress, and ferroptosis in myocardial tissues. However, the influences of AF were overturned by the co-treatment of AF and LY294002. AF activated the AKT/Nrf2/HO-1 signaling pathway in myocardial tissues in vivo. CONCLUSIONS: AF could curb cardiac myocytes ferroptosis, thus diminishing the EE-induced myocardial injury through activating the AKT/Nrf2/HO-1 cascade.

The Ubiquity of the Reaction of the Labile Iron Pool That Attenuates Peroxynitrite-Dependent Oxidation Intracellularly.

Although the labile iron pool (LIP) biochemical identity remains a topic of debate, it serves as a universal homeostatically regulated and essential cellular iron source. The LIP plays crucial cellular roles, being the source of iron that is loaded into nascent apo-iron proteins, a process akin to protein post-translational modification, and implicated in the programmed cell death mechanism known as ferroptosis. The LIP is also recognized for its reactivity with chelators, nitric oxide, and peroxides. Our recent investigations in a macrophage cell line revealed a reaction of the LIP with the oxidant peroxynitrite. In contrast to the LIP's pro-oxidant interaction with hydrogen peroxide, this reaction is rapid and attenuates the peroxynitrite oxidative impact. In this study, we demonstrate the existence and antioxidant characteristic of the LIP and peroxynitrite reaction in various cell types. Beyond its potential role as a ubiquitous complementary or substitute protection system against peroxynitrite for cells, the LIP and peroxynitrite reaction may influence cellular iron homeostasis and ferroptosis by changing the LIP redox state and LIP binding properties and reactivity.

Endothelial cell ferroptosis influences IDH wild-type glioblastoma growth in recurrent glioblastoma multiforme patients.

Glioblastomas are known for their poor clinical prognosis, with recurrent tumors often exhibiting greater invasiveness and faster growth rates compared to primary tumors. To understand the intratumoral changes driving this phenomenon, we employed single-cell sequencing to analyze the differences between two pairs of primary and recurrent glioblastomas. Our findings revealed an upregulation of ferroptosis in endothelial cells within recurrent tumors, identified by the significant overexpression of the NOX4 gene. Further analysis indicated that knocking down NOX4 in endothelial cells reduced the activity of the ferroptosis pathway. Utilizing conditioned media from endothelial cells with lower ferroptosis activity, we observed a decrease in the growth rate of glioblastoma cells. These results highlighted the complex role of ferroptosis within tumors and suggested that targeting ferroptosis in the treatment of glioblastomas requires careful consideration of its effects on endothelial cells, as it may otherwise produce counterproductive outcomes.

The phenol red compound: A potential artifact in pharmacological induction of ferroptosis.

Phenol red (PR) is a commonly used compound in culture media as a pH indicator. However, it is unknown whether this compound can interfere with the pharmacological induction of ferroptosis. Here, using high-content live-cell imaging death analysis, we determined that the presence of PR in the culture medium preconditioned normal and tumor cells to ferroptosis induced by system xc- inhibition mediated by imidazole ketone erastin (IKE) or GPX4 blockade in response to RSL-3, but had no significant effects against treatment with the endoperoxide FINO2. Mechanistically, we revealed that PR decreases the levels of the antiferroptotic genes Slc7a11, Slc3a2, and Gpx4, while promoting the overexpression de Acls4, a key inducer of ferroptosis. Additionally, through superresolution analysis, we determined that the presence of PR mislocalizes the system xc- from the plasma membrane. Thus, our results show that the presence of PR in the culture medium can be a problematic artifact for the accurate interpretation of cell sensitivity to IKE or RSL-3-mediated ferroptosis induction.

Ferrostatin-1 mitigates cellular damage in a ferroptosis-like environment in Caenorhabditis elegans.

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2+, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: (i) Fe2+ overload, (ii) glutathione peroxidase 4 inactivation, (iii) lipid peroxidation, and (iv) glutathione depletion. The present study sought to evaluate the consequences of Fe2+ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2+ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 µM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2+ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2+ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype.

A multi-platform analysis of human gingival crevicular fluid reveals ferroptosis as a relevant regulated cell death mechanism during the clinical progression of periodontitis.

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

Keap1/Nrf2 signaling pathway participating in the progression of epilepsy via regulation of oxidative stress and ferroptosis in neurons.

OBJECTIVE: This study aims to analyze the relationship between the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) and Epilepsy (EP), as well as its mechanism of action. METHODS: Thirty Wistar rats were divided into a control group (without treatment), a model group (EP modeling), and an inhibition group (EP modeling + intervention by Keap1/Nrf2 signaling pathway inhibitor ATRA) and subject to Morris water maze experiment. Then, the expression of Oxidative Stress (OS) markers, ferroptosis-associated proteins and Keap1/Nrf2 pathway in rat hippocampus was measured. In addition, rat hippocampal neuronal cell HT22 was purchased and treated accordingly based on the results of grouping, and cell proliferation and apoptosis in the three groups were determined. RESULTS: Compared with rats in the model group, those in the inhibition group showed shorter escape latency and an increased number of platform crossings (p < 0.05). Significant OS and neuron ferroptosis, increased apoptosis rate, elevated Keap1 expression, and decreased Nrf2 expression were observed in the model group compared to the control group (p < 0.05). The inhibition group exhibited notably improved OS and ferroptosis, as well as enhanced neuronal viability (p < 0.05). CONCLUSION: Inhibition of the Keap1/Nrf2 pathway can reverse the OS and neuron viability in EP rats.

Phospholipase D regulates ferroptosis signal transduction in mouse spleen hypoxia response.

High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury.

New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment.

Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metal accumulation associated with dopaminergic neuronal death has been documented in Parkinson's disease. Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronal and glial response during iron overload. In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated in mice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevated expression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in the midbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymes was identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl ester levels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice. In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into the mechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation. We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found that the ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes. Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as a consequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest that developing therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegeneration associated with ferroptosis and brain iron accumulation.

Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury.

Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (PPAR-α antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR-α functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals.

Dehydroascorbic acid sensitizes cancer cells to system xc- inhibition-induced ferroptosis by promoting lipid droplet peroxidation.

Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers.

Puerarin alleviated oxidative stress and ferroptosis during renal fibrosis induced by ischemia/reperfusion injury via TLR4/Nox4 pathway in rats.

PURPOSE: To investigate the role of puerarin on renal fibrosis and the underlying mechanism in renal ischemia and reperfusion (I/R) model. METHODS: Rats were intraperitoneally injected with puerarin (50 or 100 mg/kg) per day for one week before renal I/R. The level of renal collagen deposition and interstitial fibrosis were observed by hematoxylin and eosin and Sirius Red staining, and the expression of α-smooth muscle actin (α-SMA) was examined by immunohistochemical staining. The ferroptosis related factors and TLR4/Nox4-pathway-associated proteins were detected by Western blotting. RESULTS: Puerarin was observed to alleviate renal collagen deposition, interstitial fibrosis and the α-SMA expression induced by I/R. Superoxide dismutase (SOD) activities and glutathione (GSH) level were decreased in I/R and hypoxia/reoxygenation (H/R), whereas malondialdehyde (MDA) and Fe2+ level increased. However, puerarin reversed SOD, MDA, GSH and Fe2+ level changes induced by I/R and H/R. Besides, Western blot indicated that puerarin inhibited the expression of ferroptosis related factors in a dose-dependent manner, which further demonstrated that puerarin had the effect to attenuate ferroptosis. Moreover, the increased expression of TLR/Nox4-pathway-associated proteins were observed in I/R and H/R group, but puerarin alleviated the elevated TLR/Nox4 expression. CONCLUSIONS: Our results suggested that puerarin inhibited oxidative stress and ferroptosis induced by I/R and, thus, delayed the progression of renal fibrosis, providing a new target for the treatment of renal fibrosis.

Animal models of kidney iron overload and ferroptosis: a review of the literature.

In recent years, it has been identified that excess iron contributes to the development of various pathologies and their complications. Kidney diseases do not escape the toxic effects of iron, and ferroptosis is identified as a pathophysiological mechanism that could be a therapeutic target to avoid damage or progression of kidney disease. Ferroptosis is cell death associated with iron-dependent oxidative stress. To study the effects of iron overload (IOL) in the kidney, numerous animal models have been developed. The methodological differences between these models should reflect the IOL-generating mechanisms associated with human IOL diseases. A careful choice of animal model should be considered for translational purposes.

Inductores de ferroptosis para el tratamiento del cáncer / Ferroptosis Inducers for Cancer Treatment

Introducción: La ferroptosis es un proceso no apoptótico de muerte celular regulada que depende de la presencia de iones hierro en el medio intracelular. Se caracterizada por la acumulación de especies reactivas de lípidos oxidados y radicales libres en las membranas celulares. Los inductores e inhibidores de este proceso inciden de manera circunstancial en él, con cuya respuesta celular se trabaja en función de elaborar modelos para el tratamiento del cáncer. Objetivo: Profundizar en el proceso de ferroptosis con un enfoque hacia los inductores e inhibidores, el establecimiento de modelos biofisicoquímicos y las estrategias terapéuticas para el tratamiento del cáncer. Métodos: Se realizó una revisión de los estudios más significativos sobre el tema, publicados en la Web of Science, PubMed, EBSCO, y Scopus. Resultados: Gracias al novedoso descubrimiento de la ferroptosis como impulsor de la muerte de células tumorales para tratar el cáncer, se han comenzado a desarrollar modelos teóricos que simulan el comportamiento de estas células y la complejidad en sistemas biológicos; que permiten encontrar procedimientos alternativos y menos invasivos contra esta y otras enfermedades. Conclusiones: Los inductores e inhibidores tienen una función primordial a la hora de predecir la influencia en la sensibilidad a la ferroptosis; por lo que se indagó en los mecanismos de funcionamiento de estos, que facilitará la forma de inducir en mayor o menor grado la muerte celular y disminuir la población de células cancerígenas(AU)

Introduction: Ferroptosis is a non-apoptotic process of regulated cell death that depends on the presence of iron ions in the intracellular medium. It is characterized by the accumulation of reactive species of oxidized lipids and free radicals in cell membranes. The inducers and inhibitors of this process circumstantially affect it, whose cellular response is used to develop models for cancer treatment. Objective: To deepen the ferroptosis process focusing on inducers and inhibitors, the establishment of biophysiochemical models and therapeutic strategies for cancer treatment. Methods: A review was carried out of the most significant studies on the subject, published in the Web of Science, PubMed, EBSCO and Scopus. Results: Thanks to the novel discovery of ferroptosis as a conductor of tumor cell death to treat cancer, theoretical models have begun to be developed that simulate the behavior of these cells and the complexity in biological systems; that allow finding alternative and less invasive procedures against this and other diseases. Conclusions: Inductors and inhibitors have a primary role in predicting the influence on sensitivity to ferroptosis; therefore, the mechanisms of operation of these were investigated, which will facilitate the way to induce cell death to a greater or lesser degree and reduce the population of cancer cells(AU)

LncRNA OTUD6B-AS1 overexpression promoted GPX4-mediated ferroptosis to suppress radioresistance in colorectal cancer.

BACKGROUND: Radiotherapy is widely employed in colorectal cancer (CRC) treatment but is often compromised by developed radioresistance. This study explored the mechanism of long non-coding RNA ovarian tumor domain containing 6B-antisense RNA1 (lncRNA OTUD6B-AS1) in CRC radioresistance through tripartite motif 16 (TRIM16). METHODS: CRC and non-cancerous tissues were collected and radioresistant CRC cells were established, with real-time quantitative polymerase chain reaction to determine gene expression in tissues and cells. Radioresistance was evaluated by cell counting kit-8 assay and immunofluorescence (γ-H2AX) and ferroptosis was tested by Western blot assay (ACSL4/GPX4) and assay kits (Fe2+/ROS/MDA/GSH). The association between ferroptosis and lncRNA OTUD6B-AS1-inhibited radioresistance was testified using ferroptosis inhibitor. The subcellular localization of lncRNA OTUD6B-AS1 was tested by the nuclear/cytoplasmic fractionation assay, with RNA immunoprecipitation assay to validate gene interactions. Rescue experiments were conducted to analyze the role of TRIM16 in CRC radioresistance. RESULTS: LncRNA OTUD6B-AS1 and TRIM16 were poorly expressed (P < 0.01) in CRC tissues and cells and further decreased (P < 0.01) in radioresistant CRC cells. OTUD6B-AS1 overexpression decreased cell survival (P < 0.01), increased γ-H2AX levels (P < 0.01), and elevated ferroptosis and oxidative stress (P < 0.01) after X-ray radiation. Ferroptosis inhibitor attenuated radioresistance (P < 0.01) caused by lncRNA OTUD6B-AS1 overexpression. LncRNA OTUD6B-AS1 stabilized TRIM16 mRNA via binding to HuR. TRIM16 knockdown reduced ferroptosis and increased radioresistance (P < 0.05). CONCLUSION: OTUD6B-AS1 overexpression stabilized TRIM16 via binding to HuR and increased GPX4-mediated ferroptosis, thus attenuating CRC radioresistance. Our study provided a new rationale for the treatment of CRC.

ALDH2 activation attenuates oxygen-glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy.

PURPOSE: It is previously reported that aldehyde dehydrogenase 2 family member (ALDH2) shows neuroprotective effects in cerebral ischemia/reperfusion injury. However, whether the protective effects are through mediating the programmed cell death is yet to be fully elucidated. METHODS: In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells and mouse cortical neurons. Subsequently, ALDH2 expression were assessed by qRT-PCR and western blot. The methylation status was examined by methylation-specific PCR (MS-PCR). Then, ALDH2 expression was promoted and suppressed to explore the role of ALDH2 in OGD/R-treated cells. CCK-8 assay was applied to detect cell viability, and flow cytometry was applied to evaluate cell apoptosis. Western blot was applied to detect the apoptosis-related proteins (Caspase 3, Bcl-2 and Bax), necroptosis-related proteins (RIP3 and MLKL), pyroptosis-related proteins (NLRP3 and GSDMD), ferroptosis-related protein (ACSL4 and GPX4), and autophagy-related proteins (LC3B, and p62). IL-1ß and IL-18 production was evaluated by ELISA assay. Reactive oxygen species production and Fe2+ content were evaluated by the corresponding detection kit. RESULTS: In OGD/R-treated cells, ALDH2 expression was decreased, which was due to the hypermethylation of ALDH2 in the promoter region. ALDH2 overexpression improved cell viability and ALDH2 knockdown suppressed cell viability in OGD/R-treated cells. We also found that ALDH2 overexpression attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy, while ALDH2 knockdown facilitated the OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. CONCLUSIONS: Collectively, our results implied that ALDH2 attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy to promote cell viability in HT22 cells and mouse cortical neurons.

Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells.

Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.

Overexpression of ferroptosis-related genes FSP1 and CISD1 is related to prognosis and tumor immune infiltration in gastric cancer.

PURPOSE: Gastric cancer (GC) is one of the highest incidence rate cancers worldwide and the search for new biomarkers remains urgent due to its relatively poor prognosis and limited treatment methods. Ferroptosis suppressor protein 1 (FSP1) and iron sulfur domain 1 (CISD1) promoted malignant tumor progression as ferroptosis suppressors in a variety of tumors, but their study in GC remains to be explored. METHODS: In our study, FSP1 and CISD1 expression were predicted through different databases and confirmed by qRT-PCR, immunohistochemistry and western blotting. Enrichment analyses were exploited to explore the potential functions of FSP1 and CISD1. Finally, their relationship with immune infiltration was determined by Tumor Immune Estimation Resource and ssGSEA algorithm. RESULTS: The expression of FSP1 and CISD1 was higher in GC tissues. Their strongly positive immunostaining was associated with increased tumor size, degree of differentiation, depth of invasion and lymph node metastasis in GC patients. Up-regulated FSP1 and CISD1 predicted poorer overall survival of patients with GC. Furthermore, FSP1 and CISD1 as ferroptosis inhibitors were predicted to be involved in GC immune cell infiltration. CONCLUSIONS: Our study suggested that FSP1 and CISD1 acted as biomarkers of poor prognosis and promising immunotherapeutic targets for GC.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

PURPOSE: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. METHODS: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nick-end labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. RESULTS: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. CONCLUSIONS: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.