Peroxide Accumulation Research Articles

Repurposing flubendazole for glioblastoma ferroptosis by affecting xCT and TFRC proteins.

New uses of old drugs hold great promise for clinical translation. Flubendazole, an FDA-approved antiparasitic drug, has been shown to target p53 and promote apoptosis in glioblastoma (GBM) cells. However, its damaging mechanism in GBM remains elusive. Herein, we explored the ferroptosis-inducing ability of flubendazole on GBM cells. After treating glioma cell lines U251 and LN229 with the flubendazole (DMSO <1‰), cell viability was inhibited in a concentration-dependent manner (IC50 for LN229 = 0.5331 μM, IC50 for U251 = 0.6809 μM), attributed to the induction of ferroptosis, as evidenced by increased MDA levels, accumulation of ROS and lipid peroxides, change in mitochondrial membrane potential and structure. Protein analysis related to ferroptosis showed upregulation of TFRC, DMT1 and p53, alongside downregulation of xCT, FHC and GPX4 (p < 0.05). All-atom docking studies demonstrated that flubendazole bound closely with xCT, and TFRC, validating its role in inducing glioma ferroptosis via modulation of these proteins. Notably, flubendazole could damage the glioblastoma stem cells (GSC) that are typically resistant to other therapies, thereby possessing advantages in stopping glioma recurrence. This study delved into the mechanisms of flubendazole-induced ferroptosis in glioma, broadening its application and providing new ideas for new uses of other old drugs.

Critical role of non-coding RNA-mediated ferroptosis in urologic malignancies.

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, a novel mode of cell death, typically arises from intracellular iron ion overload and the accumulation of lipid peroxides. This process has been shown to play a crucial regulatory role in various pathological conditions, particularly in cancer, including urologic cancers. However, the comprehensive regulatory mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application in cancer therapy. Non-coding RNAs (ncRNAs), which encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are non-coding transcripts that play pivotal roles in various physiological processes, such as proliferation, differentiation, apoptosis, and cell cycle regulation, by modulating the expression of target genes. The biological functions and potential regulatory mechanisms of ncRNAs in the context of cancer-related ferroptosis have been partially elucidated. Research indicates that ncRNAs can influence the progression of urologic cancers by affecting cell proliferation, migration, and drug resistance through the regulation of ferroptosis. Consequently, this review aims to clarify the functions and mechanisms of the ncRNA-ferroptosis axis in urologic cancers and to evaluate the clinical significance of ferroptosis-related ncRNAs, thereby providing new insights into cancer biology and therapeutic strategies that may ultimately benefit a diverse range of cancer patients.

Inhibiting Ferroptosis Prevents the Progression of Steatotic Liver Disease in Obese Mice.

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Interactions Between Ferroptosis and Oxidative Stress in Ischemic Stroke.

Ischemic stroke is a devastating condition that occurs due to the interruption of blood flow to the brain, resulting in a range of cellular and molecular changes. In recent years, there has been growing interest in the role of ferroptosis, a newly identified form of regulated cell death, in ischemic stroke. Ferroptosis is driven by the accumulation of lipid peroxides and is characterized by the loss of membrane integrity. Additionally, oxidative stress, which refers to an imbalance between prooxidants and antioxidants, is a hallmark of ischemic stroke and significantly contributes to the pathogenesis of the disease. In this review, we explore the interactions between ferroptosis and oxidative stress in ischemic stroke. We examine the underlying mechanisms through which oxidative stress induces ferroptosis and how ferroptosis, in turn, exacerbates oxidative stress. Furthermore, we discuss potential therapeutic strategies that target both ferroptosis and oxidative stress in the treatment of ischemic stroke. Overall, this review highlights the complex interplay between ferroptosis and oxidative stress in ischemic stroke and underscores the need for further research to identify novel therapeutic targets for this condition.

Development of a complex antioxidant for stabilization of dressing enriched with omega-3 fatty acids

The solution to the problem of developing a complex antioxidant for the oxidative stabilization of emulsion systems with a high content of ω-3 polyunsaturated fatty acids (PUFAs) is considered. The object of the study is the oxidative stabilization of dressing using a complex antioxidant of plant origin. The ratio of ω-3:ω-6 PUFAs in model samples of the emulsion system was 1:5.46 and 1:2.21. The reasonable range of antioxidant ratios in the complex was substantiated. The ratio of tocopherol extract, garlic and laurel essential oils in the complex antioxidant is 1:1:1, respectively. Over 30 days of storage of the emulsion system model samples stabilized with a complex antioxidant, there is a gradual accumulation of organic acids (from 0.73 % to 0.75 %). The content of primary oxidation products increases for sample No. 2 – from 0.7 to 1.9 mmol ½ O2/kg, for sample No. 3 – from 0.4 to 1.2 mmol ½ O2/kg. The obtained values of physicochemical parameters meet the requirements of regulatory documentation (DSTU 4561). The peculiarity of the obtained results is that the complex antioxidant showed a significant increase in the stability of the emulsion system of high nutritional value, in particular, slowed down the accumulation of organic acids and peroxides. From a practical point of view, the development can effectively stabilize food emulsion systems with a high content of oxidation-labile PUFAs. An applied aspect of the obtained scientific result is the possibility of modeling and developing new formulations of emulsion and individual fat systems with high nutritional value, containing high PUFA concentrations

The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders.

Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.

Neurotoxic and developmental effects of scented incense stick smoke: Network toxicology and zebrafish model study

Burning incense sticks is a traditional practice in many cultures, especially in Southeast Asia. While it is often regarded as sacred and beneficial, modern incense sticks contain various chemicals that can pose health risks. A GCMS analysis of the ICS revealed potential compounds. Network toxicology revealed that ICS contains compounds violating Lipinski's rule of five, leading to potential neurotoxic effects. Key pathways affected include neuroactive ligand-receptor interaction and calcium signaling, associated with neurodegenerative diseases like Parkinson's and Alzheimer's. Significant genes involved are STAT3, BCL2, and MTOR, emphasizing the chemical hazards of ICS exposure. We investigated the toxicity of ICS using zebrafish (Danio rerio) embryos as a mode. ICS exposure resulted in a dose-dependent increase in toxicity. High concentrations (7 and 14 µg/ml) led to immediate mortality, while lower concentrations (0.1, 0.3, 0.5, and 1 µg/ml) caused developmental defects such as yolk sac edema, skeletal malformations, and pericardial edema. Mortality rates increased with higher concentrations, confirming dose-dependent ICS exposure caused hypoactive locomotion, with reduced distance traveled and velocity toxicity. Higher concentrations of ICS led to increased ROS levels and cellular damage, as evidenced by enhanced staining levels. A dose-dependent increase in lipid peroxidation (DPPP assay) and lipid accumulation (Nile red assay) was observed. Higher ICS concentrations led to significant oxidative damage to lipids and increased lipid deposition. Enzymatic assays showed that ICS exposure significantly decreased the activities of antioxidant enzymes SOD and CAT, indicating impaired antioxidant defense, while increasing LDH activity, signaling tissue damage and cytotoxicity. Gene expression analysis revealed downregulation of SOD1 and CAT genes, upregulation of inflammatory genes TNF-α and IL-1β, and increased expression of the apoptotic gene p53 with decreased expression of Bcl-2 and BDNF. These findings highlight ICS's potential to cause oxidative stress, inflammation, apoptosis, and neurodevelopmental impairments.

Rtlp2 enhances thermotolerance in rice

The harmful effects of heat stress on agricultural production are becoming increasingly severe. Thaumatin-like proteins (TLPs) have been demonstrated to play crucial roles in regulating plant resistance to biotic and abiotic stresses. However, their involvement in plant thermotolerance is poorly understood. This study aims to investigate the major-effect gene in a key quantitative trait locus (QTL) associated with rice thermotolerance, namely Rtlp2, which encodes a rice TLP. The Rtlp2 protein was found to be localized in the endoplasmic reticulum (ER). Rice seedlings overexpressing the Rtlp2 gene showed significantly enhanced thermotolerance compared to the wild type, while rtlp2 mutant exhibited increased susceptibility to heat stress. After 48 h of heat stress treatment, rice plants overexpressing Rtlp2 exhibited reduced accumulation of hydrogen peroxide (H2O2) and cell death compared to the wild-type. Conversely, the mutant plants showed the opposite behavior. The results of gene expression level analyses revealed that Rtlp2 positively regulates rice thermotolerance through the modulation of rice heat shock transcription factors (HSFs) and heat shock proteins (HSPs) network. After undergoing natural heat stress in the field, the rice lines overexpressing Rtlp2 showed higher seed setting rate and yield per plant compared to the wild-type. In addition, Rtlp2 has also been found to positively regulate grain length and grain weight in rice. This study provides valuable resources for addressing the challenge of increasing environmental heat and promoting the breeding of heat-tolerant rice varieties.

Effects of nickel, lead, and copper stress on the growth and biochemical responses of Aegilops tauschii seedlings

Heavy metal pollution causes severe abiotic stress in cereal crops around the world. This study investigated the effects of different concentrations (0, 100, 200, and 300 mg·kg–1) of nickel, lead, and copper stress on the growth and biochemical responses of Aegilops tauschii seedlings, to provide a reference for research on the mechanism of invasion and screening potential sources of wheat tolerance genes. The results showed that nickel, lead, and copper stress caused a significant decrease in the contents of chlorophyll a, chlorophyll b, and chlorophyll (a + b) in A. tauschii, thereby inhibiting photosynthesis to different degrees and hindering seedling growth, which was reflected in significant reductions in plant height and root length, with the most notable effect observed under stress by 300 mg·kg–1 lead. As the concentration of heavy metals increased, the activities of antioxidant enzymes (SOD, POD, and APX), non-enzymatic antioxidants (GSH and AsA), and the contents of osmotic regulatory substances (proline and soluble proteins) in A. tauschii significantly increased. Additionally, heavy metal stress increased H2O2 and TBARS levels. However, when the nickel, lead, and copper concentrations reached 300 mg·kg–1, no significant differences were found in H2O2 or TBARS levels compared to those in the CK group. To summarize, A. tauschii can mitigate the accumulation of ROS and membrane lipid peroxidation caused by heavy metal stress through self-regulation, thus exhibiting a certain degree of tolerance to stress caused by different concentrations of nickel, lead, and copper. Finally, the evaluation using the membership function method revealed that among the three heavy metals, A. tauschii exhibited the strongest adaptation to Cu, followed by Ni and Pb.

Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis

AbstractFerroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases, underscoring the urgent need to develop effective ferroptosis inhibitors. Although Ferrostatin‐1 (Fer‐1) is a potent ferroptosis inhibitor, its susceptibility to oxidation and metabolic inactivation limits its clinical utility. In this study, the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin‐1 prodrugs with reactive oxygen species‐responsive features. This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas, allowing for targeted release and improved stability. The novel compounds demonstrated significant inhibitory effects and selectivity against RSL‐3‐induced ferroptosis in HK‐2 cells, with compound a1 exhibiting an EC50 of 15.4 ± 0.7 μM, outperforming Fer‐1. These compounds effectively identify the oxidative microenvironment associated with ferroptosis, enabling the targeted release of Fer‐1, which prevents lipid peroxide accumulation and inhibits ferroptosis. This strategy holds promise for treating diseases related to ferroptosis, offering a targeted and intelligent therapeutic approach.

Dynamics of Hydrogen Peroxide Accumulation During Tip Growth of Infection Thread in Nodules and Cell Differentiation in Pea (Pisum sativum L.) Symbiotic Nodules.

Hydrogen peroxide (H2O2) in plants is produced in relatively large amounts and plays a universal role in plant defense and physiological responses, including the regulation of growth and development. In the Rhizobium-legume symbiosis, hydrogen peroxide plays an important signaling role throughout the development of this interaction. In the functioning nodule, H2O2 has been shown to be involved in bacterial differentiation into the symbiotic form and in nodule senescence. In this study, the pattern of H2O2 accumulation in pea (Pisum sativum L.) wild-type and mutant nodules blocked at different stages of the infection process was analyzed using a cytochemical reaction with cerium chloride. The observed dynamics of H2O2 deposition in the infection thread walls indicated that the distribution of H2O2 was apparently related to the stiffness of the infection thread wall. The dynamics of H2O2 accumulation was traced, and its patterns in different nodule zones were determined in order to investigate the relationship of H2O2 localization and distribution with the stages of symbiotic nodule development in P. sativum. The patterns of H2O2 localization in different zones of the indeterminate nodule have been partially confirmed by comparative analysis on mutant genotypes.

Targeting Ferroptosis with Small Molecule Atranorin (ATR) as a Novel Therapeutic Strategy and Providing New Insight into the Treatment of Breast Cancer

Background/Objectives: Ferroptosis results from the accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Previous research has determined the effect of atranorin (ATR) on other cell death mechanisms, but its potential for a ferroptotic effect depending on ROS levels is unclear. This study details the therapeutic role of small-molecule ATR through ferroptosis by suppressing MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cells. Methods: The anti-proliferative effect of ATR on cells was evaluated by xCELLigence analysis, and ferroptotic activity was evaluated by enzymatic assay kits. The changes in gene and protein expression levels of ATR were investigated by the qRT-PCR and western blot. In addition, mitochondrial changes were examined by transmission electron microscopy. Results: ATR was found to reduce cell viability in cancer cells in a dose- and time-dependent manner without showing cytotoxic effects on normal breast cells. In BT-474 and MDA-MB-231 cells, ATR, which had a higher anti-proliferative effect, increased iron, lipid peroxidation, and ROS levels in cells and decreased the T-GSH/GSSG ratio. The results revealed for the first time that small-molecule ATR exhibited anti-cancer activity by inducing the glutathione pathway and ferroptosis. Conclusions: This study highlights the potential of ATR as a drug candidate molecule that can be used in the development of new therapeutic strategies for the treatment of triple-negative and luminal-B breast cancer subtypes.

Physiological and Microstructure Analysis Reveals the Mechanism by Which Formic Acid Delays Postharvest Physiological Deterioration of Cassava.

Formic acid is reported to act as a food preservative and feed additive, but its effects on controlling postharvest physiological deterioration (PPD) development in cassava are unclear. In this study, we assessed the effectiveness of different concentrations of formic acid in attenuating PPD occurrence in fresh-cut cassava. The results showed that the concentration of 0.1% (v/v) formic acid could significantly delay the occurrence of PPD, and that the higher the concentration of formic acid supplied, the later the occurrence of PPD symptoms. The physiological and biochemical analysis of 0.5%-formic-acid-treated cassava slices revealed that formic acid decreased the degradation of starch, inhibited the accumulation of hydrogen peroxide (H2O2), malondialdehyde (MDA), and water-soluble pectin in cassava slices with PPD development, and increased the activities of the antioxidant enzymes ascorbate peroxidase (APX) and glutathione reductase (GR). A microscopic observation showed that the formic acid treatment inhibited the enlargement of the intercellular space during the cassava PPD process, which suggests that the formation of an intercellular layer of the cell wall was inhibited by formic acid. This study thus revealed the mechanism used by formic acid to extend the cassava shelf life; however, a detailed evaluation of the possible side effects on, for example, the cyanide content will be needed to categorically ensure the safety of this method.

Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins

Malignant cells exhibit a high demand for amino acids to sustain their abnormal proliferation. Particularly, the intracellular accumulation of cysteine is often observed in cancer cells. Previous studies have shown that deprivation of intracellular cysteine in cancer cells results in the accumulation of lipid peroxides in the plasma membrane and induction of ferroptotic cell death, indicating that cysteine plays a critical role in the suppression of ferroptosis. Herein, we found that the oncogenic accumulation of cysteine also contributes to cancer cell proliferation by promoting the cell cycle progression, which is independent of its suppressive effect on ferroptosis. The growth ability of four types of cancer cells, including murine hepatocarcinoma cells, but not of primary hepatocytes, were dependent on the exogenous supply of cysteine. Deprivation of intracellular cysteine in cancer cells induced cell cycle arrest at the G0/G1 phase, accompanied by a decrease in the expression of cyclin D1 and D2 proteins. The cysteine deprivation-induced decrease in D-type cyclin expression was associated with the upregulation of eukaryotic translation initiation factor 4E binding protein (4E-BP1), which represses the translation of cyclin D1 and D2 proteins by binding to eukaryotic translation initiation factor 4E (eIF4E). Similar results were observed in hepatocarcinoma cells treated with erastin, an xCT inhibitor. These findings reveal an unappreciated role of cysteine in regulating the growth of malignant cancer cells and deepen our understanding of the cytotoxic effect of xCT inhibitor to prevent cancer cell proliferation.

Targeting Ferroptosis: Small-molecule Inducers as Novel Anticancer Agents.

Ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, is increasingly recognized for its role in cancer development and as a potential therapeutic target. This review consolidates insights into the molecular mechanisms underpinning ferroptosis and evaluates the therapeutic potential of small-molecule inducers, such as erastin, RSL3, sulfasalazine, and sorafenib, which selectively trigger ferroptosis in cancer cells. It highlights the distinct morphological and molecular signatures of ferroptosis, its complex interplay with iron, lipid, and amino acid metabolic pathways, and the resultant implications for cancer treatment strategies. Strategic manipulation of the ferroptosis pathway offers a groundbreaking approach to cancer treatment, potentially circumventing the resistance that cancers develop against traditional apoptosis-inducing agents. Furthermore, it also emphasizes the necessity of refining these small molecules for clinical application and exploring their synergistic potential when combined with current therapies to augment overall treatment efficacy and improve patient outcomes. Ferroptosis thus emerges as a promising avenue in the realm of cancer therapy. Moving forward, research endeavors should focus on a more nuanced understanding of the interconnections between ferroptosis and other cell death modalities. Additionally, comprehensive evaluations of the long-term safety and therapeutic indices of the involved compounds are imperative. Such investigations are poised to herald a transformative shift in the paradigm of oncology, paving the way for innovative and targeted interventions.

Glutathione-Depleted Photodynamic Nanoadjuvant for Triggering Nonferrous Ferroptosis to Amplify Radiotherapy of Breast Cancer.

Radiotherapy plays a crucial role in the treatment of advanced breast cancer, but the increased antioxidant system, especially the rise in glutathione (GSH), presents a significant obstacle to its effectiveness. To address this challenge, a versatile GSH-depleted photodynamic nanoadjuvant is developed to augment the efficacy of radiotherapy for breast cancer treatment. This nanoadjuvant operates within the tumor microenvironment to effectively deplete intracellular GSH through a sequence of cascaded processes, including GSH exhaustion, biosynthetic inhibition, and photodynamic oxidation. This leads to a notable accumulation of lipid peroxides (LPO) and subsequent suppression of glutathione peroxidase 4 (GPX4) activity. Consequently, the combined GSH depletion induced by the nanoadjuvant markedly promotes nonferrous ferroptosis, thereby contributing to the augmentation of antitumor efficiency during radiotherapy in breast cancer. This work presents an innovative approach to designing and synthesizing biocompatible nanoadjuvants with the goal of improving the efficacy of radiotherapy for breast cancer in prospective clinical scenarios.

A Specific Targeted Enhanced Nanotherapy Strategy for Inducing Ferroptosis by Regulating the Iron Pool Levels in Tumor Cells.

Ferroptosis is an iron-dependent cell death pathway triggered by the toxic accumulation of lipid peroxides on cellular membranes. However, an imbalance in iron metabolism in tumor cells leads to the insufficient accumulation of iron ions in the iron pool, which inhibits ferroptosis. Nonspecific delivery of iron species may increase the risk of promoting tumor proliferation as well as trigger undesirable detrimental effects such as anaphylactic reactions in normal tissues. This study found that a constructed self-enhancing targeted nanocarrier can accurately regulate the iron pool levels in tumor cells. We constructed a programmatic targeted enhanced nanotherapy strategy by loading the ferroptosis inducer erastin into a self-enhancing targeted nanocarrier. This nanosystem was more effective at inducing tumor ferroptosis after upregulating the iron pool levels in tumor cells with self-enhancing targeted nanocarriers. Both in vitro and in vivo outcomes demonstrated notable anticancer ferroptosis efficacy, indicating that self-enhancing targeted nanocarriers can effectively regulate the level of the iron pool in tumor cells and promote ferroptosis. The combination of this nanotherapy strategy with self-enhancing targeted chemotherapy nanomedicines can achieve complete tumor clearance. Moreover, this self-enhancing targeted ferroptosis nanotherapy strategy is expected to be beneficial for future progress in the field of cancer self-enhancing targeted therapy.

MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import.

Ferroptosis is a recently identified iron-dependent programmed cell death with lipid peroxide accumulation and condensation and compaction of mitochondria. A recent study indicated that ferroptosis plays a pivotal role in ischemic cardiac injury with the mechanisms remain largely unknown. This study demonstrates that when an iron overload occurs in the ischemia/reperfusion cardiac tissues, which initiates myocardial ferroptosis, the expression levels of mitochondrial inner membrane protein MPV17 are reduced. Overexpression of MPV17 delivered via adenovirus significantly reduced ferroptosis in both cardiomyocytes with high levels of iron and cardiac I/R tissues. Mitochondrial glutathione (mtGSH), crucial for reactive oxygen species scavenging and mitochondrial homeostasis maintenance, is depleted in myocardial ferroptosis caused by iron overload. This mechanistic study shows that MPV17 can increase mitochondrial glutathione levels through maintaining the protein homeostasis of SLC25A10, which is a mitochondrial inner-membrane glutathione transporter. The absence of MPV17 in iron overload resulted in the ubiquitination-dependent degradation of SLC25A10, leading to impaired mitochondrial glutathione import. Moreover, we found that MPV17 was the targeted gene of Nrf2, which plays a pivotal role in preventing lipid peroxide accumulation and ferroptosis. The decreased expression levels of Nrf2 led to the inactivation of MPV17 in iron overload-induced myocardial ferroptosis. In summary, this study demonstrates the critical role of MPV17 in protecting cardiomyocytes from ferroptosis and elucidates the Nrf2-MPV17-SLC25A10/mitochondrial glutathione signaling pathway in the regulation of myocardial ferroptosis.

Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4

Glioblastoma (GBM) is the most common primary intracranial malignant tumor. Recent literature suggests that induction of programmed death has become a mainstream cancer treatment strategy, with ferroptosis being the most widely studied mode. Complement C5a receptor 1 (C5aR1) is associated with both tumorigenesis and tumor-related immunity. However, knowledge regarding the role of C5aR1 in GBM progression is limited. In the present study, we observed significant upregulation of C5aR1 in glioma tissue. In addition, C5aR1 expression was found to be closely associated with patient prognosis and survival. Subsequent experimental verification demonstrated that C5aR1 promoted the progression of GBM mainly by suppressing ferroptosis induction, inhibiting the accumulation of lipid peroxides, and stabilizing the expression of the core antiferroptotic factor glutathione peroxidase 4 (GPX4). Aberrant N6-methyladenosine (m6A) modification of GPX4 mRNA contributes significantly to epigenetic tumorigenesis, and here, we report that selective methyltransferase-like 3 (METTL3)-dependent m6A methylation of GPX4 plays a key role in C5AR1 knockdown-induced ferroptosis induction. Mechanistically, ERK1/2 signaling pathway activation increases the METTL3 protein abundance in GBM cells. This activation then increases the stability of METTL3-mediated m6A modifications on GPX4, enabling it to fulfill its transcriptional function. More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression. In conclusion, our findings suggest that C5aR1 inhibits ferroptosis in GBM cells and promotes MettL3-dependent GPX4 expression through ERK1/2, thereby promoting glioma progression. Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma.

Proteomics fingerprinting reveals importance of iron and oxidative stress in Streptomyces scabies-Solanum tuberosum interactions.

The Gram-positive actinobacterium Streptomyces scabies is the major causal agent of potato common scab. The main pathogenicity factor is thaxtomin A, a phytotoxin that causes atypical cell death, although other secondary metabolites have been described to play a role in S. scabies virulence. Despite this, many aspects of the interaction between S. scabies and its primary host Solanum tuberosum L. remain to be elucidated. Intracellular proteins of S. scabies EF-35 grown in the presence of in vitro produced tubers (microtubers) of the Russet Burbank and Yukon Gold potato cultivars were extracted and analysed by electrospray mass spectrometry (ES MS/MS). Based on the results of proteomic analysis, iron quantification by ICP-MS and nitrite quantification using Griess reagent in growth media as well as RT-qPCR analysis of the siderophore pyochelin gene expression were performed in the presence and absence of microtubers. Hydrogen peroxide accumulation was also determined in the nutrient medium used for co-cultivation of bacteria and potato microtubers. Potato microtubers caused an increase in the content of bacterial proteins involved in stress and defense, secondary metabolism, and cell differentiation, as well as secreted proteins. Co-cultivation with potato microtubers induced the accumulation of S. scabies proteins implicated in siderophore pyochelin biosynthesis, nitrite production and oxidative stress perception and response. The increase in the abundance of proteins related to pyochelin biosynthesis was consistent with a significant decrease in the iron content in the culture medium, as well as with induction of expression of pyochelin biosynthesis genes. Elevated nitrite/sulfite reductase protein levels were associated with increased nitrite excretion by S. scabies cells in the presence of host microtubers. The increase in the levels of proteins associated with signaling and oxidative stress response could have been caused by the accumulation of ROS, in particular hydrogen peroxide, detected in the studied system. These findings show that interactions of S. scabies with living potato microtubers induce the production of secondary metabolites, defense responses, and protection from oxidative stress. This study suggests the importance of iron during host - S. scabies interactions, resulting in competition between pathogen and its host.