Accumulation Of Lipid Hydroperoxides Research Articles

GPX4 overexpression does not alter atherosclerotic plaque development in ApoE knock-out mice.

Ferroptosis is a type of regulated necrosis that is associated with iron-dependent accumulation of lipid hydroperoxides. Given that iron deposition and lipid peroxidation initiate ferroptosis in atherosclerosis and contribute to further plaque development, we hypothesized that inhibition of ferroptosis could be of value in the treatment of atherosclerosis. Glutathione peroxidase 4 (GPX4) is the only enzyme known capable of reducing lipid hydroperoxides. Previous studies have demonstrated that inactivation of GPX4 results in ferroptosis, while overexpression of GPX4 confers resistance to ferroptosis. In the present study, we examined the impact of GPX4 overexpression on the development of atherosclerotic plaques. GPX4-overexpressing mice (GPX4Tg/+) were crossbred with ApoE-/- mice and fed a western-type diet for 16 weeks. Atherosclerotic plaques of GPX4Tg/+ ApoE-/- mice showed increased GPX4 expression and a reduced amount of lipid hydroperoxides. However, plaque size and composition were not different as compared to control animals. Similarly, GPX4-overexpressing vascular smooth muscle cells and bone marrow-derived macrophages were not protected against lipid peroxidation and cell death triggered by the ferroptosis inducers erastin and 1S,3R-RSL3. We concluded that GPX4 overexpression reduces lipid peroxidation in plaques of ApoE-/- mice, yet GPX4 overexpression is not sufficiently powerful to change plaque size or composition.

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes.

Ischemic cardiomyopathy (ICM) is a serious cardiac disease with a very high mortality rate worldwide, which causes myocardial ischemia and hypoxia as the main damage. Further understanding of the underlying pathological processes of cardiomyocyte injury is key to the development of cardioprotective strategies. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid hydroperoxides to lethal levels, resulting in oxidative damage to the cell membrane. The current understanding of the role and regulation of ferroptosis in ICM is still limited, especially in the absence of evidence from large-scale transcriptomic data. Through comprehensive bioinformatics analysis of human ICM transcriptome data obtained from the Gene Expression Omnibus database, the present study identified differentially expressed ferroptosis-related genes (DEFRGs) in ICM. Subsequently, their potential biological mechanisms and cross-talk were analyzed, and hub genes were identified by constructing protein-protein interaction networks. Ferroptosis features such as reactive oxygen species generation, changes in ferroptosis marker proteins, iron ion aggregation and lipid oxidation, were identified in the H9c2 anoxic reoxygenation injury model. Finally, the diagnostic ability of Gap junction alpha-1 (GJA1), Solute carrier family 40 member 1 (SLC40A1), Alpha-synuclein (SNCA) were identified through receiver operating characteristic curves and the expression of DEFRGs was verified in an in vitro model. Furthermore, potential drugs (retinoic acid) that could regulate ICM ferroptosis were predicted based on key DEFRGs. The present article presents new insights into the role of ferroptosis in ICM, investigating the regulatory role of ferroptosis in the pathological process of ICM and advocating for ferroptosis as a potential novel therapeutic target for ICM based on evidence from the ICM transcriptome.

Revealing the Ferroptotic Phenotype of Medulloblastoma.

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.

Exogenous carbon monoxide promotes GPX4-dependent ferroptosis through ROS/GSK3β axis in non-small cell lung cancer

The gas therapy is drawing increasing attention in the treatment of many diseases including cancer. As one of gas signaling molecules, carbon monoxide (CO) has been proved to exert anti-cancer effects via triggering multiple cell death types, such as autophagy, apoptosis and necrosis. Here, we showed that low concentration CO delivered from CO-releasing molecule 3 (CORM-3) effectively induced ferroptosis, known as a novel proinflammatory programmed cell death, in vitro and in vivo. Mechanistically, we found that CO triggered ferroptosis by modulating the ROS/GSK3β/GPX4 signaling pathway, resulting in the accumulation of lipid hydroperoxides and the occurrence of ferroptosis. We think our findings provide novel insights into the anti-cancer mechanisms of CO, and suggest that CO could potentially be exploited as a novel ferroptosis inducer for cancer treatment in the future.

Arabinoxylan hydrolysates improved physical and oxidative stability of oil-in-water emulsions

This study was to improve the physical and oxidative stability of sodium caseinate (NaCas)-stabilized oil-in-water (O/W) emulsions with arabinoxylan hydrolysates (AXHs). AXHs with different molecular sizes were prepared using xylanase treatment for 0 (AXH0), 30 (AXH30), 60 (AXH60), and 120 (AXH120) min, respectively. Compared with the emulsion without AXHs, all AXHs emulsions showed increased coalescence stability, evidenced by no change occurred in the droplet size with the pH variation from 7.0 to 5.0. Moreover, at pH 7.0 and 5.0, AXH60 and AXH120 emulsions showed no flocculation, coalescence, or creaming before and after 21 d storage. All the AXH samples showed excellent antioxidant capacities, demonstrated by the slow accumulation of lipid hydroperoxides and thiobarbituric acid reactive substances during storage. In sum, rice bran arabinoxylans hydrolyzed ≥60 min possess a potential as effective antioxidants to form physically and oxidatively stable O/W emulsions at pH above the emulsifier pI, and substances with high antioxidant activity below the emulsifier pI still need to be explored.

Interfacial effects of gallate alkyl esters on physical and oxidative stability of high fat fish oil-in-water emulsions stabilized with sodium caseinate and OSA-modified starch.

Effects of sodium caseinate (SC) and its combination with OSA-modified starch (SC-OS; 1:1) alone and with n-alkyl gallates (C0-C18) on the physical and oxidative stability of high-fat fish oil-in-water emulsion were evaluated. SC emulsion contained the smallest droplets and highest viscosity due to the fast adsorption at droplet surfaces. Both emulsions had non-Newtonian and shear-thinning behavior. A lower accumulation of lipid hydroperoxides and volatile compounds was found in SC emulsion due to its better Fe2+ chelating activity. The incorporated short-chain gallates (G1>G0∼G3) in SC emulsion had a strong synergistic effect against lipid oxidation compared to that of SC-OS emulsion. The better antioxidant efficiency of G1 can be related to its higher partition at the oil-water interface, while G0 and G3 had a higher partition into the aqueous phase. In contrast, G8, G12, and G16 added emulsions indicated higher lipid oxidation due to their internalization inside the oil droplets.

SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis

Sterol carrier protein 2 (SCP2) is highly expressed in human osteoarthritis (OA) cartilage, accompanied by ferroptosis hallmarks, especially the accumulation of lipid hydroperoxides (LPO). However, the role of SCP2 in chondrocyte ferroptosis remains unexplored. Here, we identify that SCP2 transports cytoplasmic LPO to mitochondria in RSL3-induced chondrocyte ferroptosis, resulting in mitochondrial membrane damage and release of reactive oxygen species (ROS). The localization of SCP2 on mitochondria is associated with mitochondrial membrane potential, but independent of microtubules transport or voltage-dependent anion channel. Moreover, SCP2 promotes lysosomal LPO increase and lysosomal membrane damage through elevating ROS. However, SCP2 is not directly involved in the cell membrane rupture caused by RSL3. Inhibition of SCP2 markedly protects mitochondria and reduces LPO levels, attenuating chondrocyte ferroptosis in vitro and alleviating the progression of OA in rats. Our study demonstrates that SCP2 mediates the transport of cytoplasmic LPO to mitochondria and the spread of intracellular LPO, accelerating chondrocyte ferroptosis.

Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis

Ferroptosis is an iron dependent form of cell death, that is triggered by the discoordination of iron, lipids, and thiols. Its unique signature that distinguishes it from other forms of cell death is the formation and accumulation of lipid hydroperoxides, particularly oxidized forms of polyunsaturated phosphatidylethanolamines (PEs), which drives cell death. These readily undergo iron-catalyzed secondary free radical reactions leading to truncated products which retain the signature PE headgroup and which can readily react with nucleophilic moieties in proteins via their truncated electrophilic acyl chains. Using a redox lipidomics approach, we have identified oxidatively-truncated PE species (trPEox) in enzymatic and non-enzymatic model systems. Further, using a model peptide we demonstrate adduct formation with Cys as the preferred nucleophilic residue and PE(26:2) +2 oxygens, as one of the most reactive truncated PE-electrophiles produced. In cells stimulated to undergo ferroptosis we identified PE-truncated species with sn-2 truncations ranging from 5 to 9 carbons. Taking advantage of the free PE headgroup, we have developed a new technology using the lantibiotic duramycin, to enrich and identify the PE-lipoxidated proteins. Our results indicate that several dozens of proteins for each cell type, are PE-lipoxidated in HT-22, MLE, and H9c2 cells and M2 macrophages after they were induced to undergo ferroptosis. Pretreatment of cells with the strong nucleophile, 2-mercaptoethanol, prevented the formation of PE-lipoxidated proteins and blocked ferroptotic death. Finally, our docking simulations showed that the truncated PE species bound at least as good to several of the lantibiotic-identified proteins, as compared to the non-truncated parent molecule, stearoyl-arachidonoyl PE (SAPE), indicating that these oxidatively-truncated species favor/promote the formation of PEox-protein adducts. The identification of PEox-protein adducts during ferroptosis suggests that they are participants in the ferroptotic process preventable by 2-mercaptoethanol and may contribute to a point of no return in the ferroptotic death process.

Inhibition of Fatty Acid β-Oxidation by Fatty Acid Binding Protein 4 Induces Ferroptosis in HK2 Cells Under High Glucose Conditions.

Ferroptosis, which is caused by an iron-dependent accumulation of lipid hydroperoxides, is a type of cell death linked to diabetic kidney disease (DKD). Previous research has shown that fatty acid binding protein 4 (FABP4) is involved in the regulation of ferroptosis in diabetic retinopathy. The present study was constructed to explore the role of FABP4 in the regulation of ferroptosis in DKD. We first detected the expression of FABP4 and proteins related to ferroptosis in renal biopsies of patients with DKD. Then, we used a FABP4 inhibitor and small interfering RNA to investigate the role of FABP4 in ferroptosis induced by high glucose in human renal proximal tubular epithelial (HG-HK2) cells. In kidney biopsies of DKD patients, the expression of FABP4 was elevated, whereas carnitine palmitoyltransferase-1A (CP-T1A), glutathione peroxidase 4, ferritin heavy chain, and ferritin light chain showed reduced expression. In HG-HK2 cells, the induction of ferroptosis was accompanied by an increase in FABP4. Inhibition of FABP4 in HG-HK2 cells changed the redox state, sup-pressing the production of reactive oxygen species, ferrous iron (Fe2+), and malondialdehyde, increasing superoxide dismutase, and reversing ferroptosis-associated mitochondrial damage. The inhibition of FABP4 also increased the expression of CPT1A, reversed lipid deposition, and restored impaired fatty acid β-oxidation. In addition, the inhibition of CPT1A could induce ferroptosis in HK2 cells. Our results suggest that FABP4 mediates ferroptosis in HG-HK2 cells by inhibiting fatty acid β-oxidation.

Abstract 6139: Clinical implication of EZH2 inhibitors in hepatocellular carcinoma

Abstract Background & Aim: Aberrant upregulation of EZH2 is frequently observed in hepatocellular carcinoma (HCC) and significantly associated with poor prognosis of HCC patients. While EZH2 inhibitors (EZH2i) are recently approved for treatment of lymphoma and sarcoma, their antitumor effect alone is not optimally efficacious against solid tumors like HCC. Ferroptosis is a newly discovered nonapoptotic type of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides in cell membrane to lethal levels. Owing to anti-cancer effects of ferroptosis, many oncogenes are known to suppress ferroptosis. However, their mechanisms in HCC are currently unknown. We aim to uncover a novel mechanism for EZH2-mediated resistance to ferroptosis in HCC. Methods: Multi-step analyses were performed with genomic data from mouse models (Ezh1/2 KO), cancer cell lines treated with EZH2i GSK126, and primary tumors including HCC to identify genetic networks or signaling/metabolic pathways associated with EZH2 in cancer cells. Functional connection of identified networks or pathways from the prediction analyses was tested in cell line models with various molecular biology approaches including western blots, colony forming assay, overexpression and/or depletion of genes of interest. Results: Gene network analysis predicted that ferroptosis pathway is inhibited by EZH2. Interestingly, lipid biosynthesis is also identified as an inhibited metabolic pathway by EZH2. Since polyunsaturated fatty acid (PUFA) is essential for executing ferroptosis, we hypothesize that EZH2 suppresses ferroptosis by inhibiting synthesis of PUFA. HCC cells with high EZH2 expression have higher IC50 values to erastin, a ferroptosis inducer, than those with low EZH2 expression. Moreover, inhibition or depletion of EZH2 sensitize HCC cells to erastin-induced ferroptotic cell death, strongly suggesting that EZH2 accounts for resistance to ferroptosis. Mechanistically, EZH2 increases H3K27me3 methylation near PUFA gene promoters, leading to suppression of PUFA gene expression and subsequently low cellular PUFA level. Most interestingly, treatment of EZH2i significantly sensitized HCC cells with high EZH2 expression to erastin-induced ferroptosis, suggesting potential therapeutic opportunity for treatment of HCC patients with high EZH2 expression. Conclusion: EZH2 is a novel suppressor of ferroptosis by negatively regulating lipid metabolism. Thus, our study provides scientific evidence for developing a novel therapeutic strategy for treatment of HCC patients with co-treatment of ferroptosis inducers and EZH2 inhibitors. Citation Format: Bo Hwa Sohn, Sung Hwan Lee, Yun Seong Jeong, Ju-Seog Lee. Clinical implication of EZH2 inhibitors in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6139.

Dissecting the biochemical and molecular-genetic regulation of diverse metabolic pathways governing aroma formation in indigenous aromatic indica rice varieties.

Aromatic rice is characterized by its distinct flavor and fragrance, imparted by more than 200 volatile organic compounds. The desirable trait of aroma relies on the type of the variety, with some varieties exhibiting considerably higher aroma content. This prompted us to undergo an exhaustive study of the aroma-associated biochemical pathways and expression of related genes, encoding the enzymes involved in those pathways in indigenous aromatic rice cultivars. The higher aroma level in aromatic rice varieties was attributed to higher transcript levels of PDH, P5CS, OAT, ODC, DAO and TPI, but lower P5CDH and BADH2, as revealed by comparative expression profiling of genes in 11 aromatic and four non-aromatic varieties. Some of the high-aroma containing varieties exhibited lower expression of SPDS and SPMS genes, concomitant with higher PAO expression. Protein immunoblot analyses showed lesser BADH2 protein accumulation in the aromatic varieties. The involvement of shikimate pathway in aroma formation was justified by higher levels of shikimic and ferulic acids due to higher expression of SK1, SK2 and ARD genes. The aromatic varieties exhibited higher expression of LOX3 and HPL, with higher corresponding enzyme activity, accompanied with lower accumulation of lipid hydroperoxides and higher level of total terpenoids, signifying the role of oxylipin pathway and terpene-related volatiles in aroma formation. The pattern of transcript level and metabolite accumulation followed the same trend in both vegetative (seedling) and reproductive (seed) tissues. Sequence analyses revealed several mutations in the upstream region and different exons and introns of BADH2 in the examined aromatic varieties. The allele specific marker system acted as fingerprint to distinguish the selected aromatic rice varieties. The cleaved amplified polymorphic sequence marker established the absence of any mutation in the 14th exon of BADH2 in the aromatic varieties. The present work clearly highlighted the biochemical and molecular-genetic mechanism of differential aroma levels which could be attributed to differential regulation of metabolites and genes, belonging to 2-acetyl-1-pyrroline, shikimate, oxylipin and terpenoid metabolic pathways in the indigenous aromatic rice varieties.

The Chains of Ferroptosis Interact in the Whole Progression of Atherosclerosis.

Atherosclerosis (AS), a category of cardiovascular disease (CVD) that can cause other more severe disabilities, increasingly jeopardizes human health. Owing to its imperceptible and chronic symptoms, it is hard to determine the pathogenesis and precise therapeutics for AS. A novel type of programmed cell death called ferroptosis was discovered in recent years that is distinctively different from other traditional cell death pathways in morphological and biochemical aspects. Characterized by iron overload, redox disequilibrium, and accumulation of lipid hydroperoxides (L-OOH), ferroptosis influences endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages, as well as inflammation, partaking in the pathology of many cardiovascular diseases such as atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. The mechanisms behind ferroptosis are so sophisticated and interwoven that many molecules involved in this procedure are unknown. This review systematically depicts the initiation and modulation of ferroptosis and summarizes the contribution of ferroptosis to AS, which may open a feasible approach for target treatment in the alleviation of AS progression.

Iron accumulation in ferroptosis and the role of lipid peroxidation in osteoarthritis

Ferroptosis is a recently discovered mode of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels, but this process was found to be inhibited by ferroptosis inhibitor-specific reverse. Osteoarthritis (OA) is the most common degenerative joint disease characterized by complex pathogenesis including mechanical overload, elevated levels of inflammatory mediators, metabolic alterations, and cellular senescence and death. Since iron accumulation and oxidative stress are common pathological features of OA, the role of ferroptosis in OA has been extensively explored. Accumulating evidence indicates that iron homeostasis and lipid peroxidation are closely related to the pathogenesis of OA. This article will focus on the mechanisms of ferroptosis and the role of iron homeostasis and lipid peroxidation in the pathogenesis of OA, summarizing recent evidence.

Cadmium chloride exposure impairs the growth and behavior of Drosophila via ferroptosis

Cadmium (Cd) is a widely distributed toxic heavy metal that enters the environment via anthropogenic mobilization and accumulates in plants and animals, causing metabolic abnormalities even mortality. Although the toxic effects and stress damage of cadmium have been investigated extensively over the past few decades, research on its ability to trigger ferroptosis, growth retardation, and behavioral abnormalities is insufficient. As a result, the effects of CdCl2 exposure on growth and development, activity and sleep, and ferroptosis in this study were examined in fruit fly (Drosophila melanogaster). When exposed to 0.5 mM CdCl2, the entire growth period from larvae to adults was prolonged, and the rates of pupation and eclosion were decreased. Additionally, CdCl2 exposure resulted in a decrease in body weight and individual size of fruit fly and high lethality rate. Moreover, CdCl2 exposure altered fruit fly behavior, including decreased activity and increased sleep duration, particularly in females. Ferrostatin-1 (Fer-1) is a potent selective ferroptosis inhibitor that effectively slows lipid hydroperoxide accumulation to rescue body size reduction and restore activity and sleep in CdCl2-exposed female flies. CdCl2 exposure could induce ferroptosis in fruit fly mechanistically, as evidenced by inhibition of Nrf2 signaling pathway, accumulation of lipid peroxidation, impairment of GPX4 antioxidant system, and upregulation of iron metabolism. Our findings suggest that Cd exposure triggers ferroptosis, which leads to growth retardation and behavioral disorders in fruit fly.

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models. Here, we systematically summarize recent advances in research on ferroptosis in I/R injury and provide a comprehensive analysis of ferroptosis-regulated genes investigated in the context of I/R, as well as the therapeutic applications of ferroptosis regulators, to provide insights into developing therapeutic strategies for this devastating disease.

NcFO: A Comprehensive Resource of Curated and Predicted ncRNAs Associated with Ferroptosis

Ferroptosis is a form of regulated cell death driven by the accumulation of lipid hydroperoxides. Regulation of ferroptosis might be beneficial to cancer treatment. Non-coding RNAs (ncRNAs) are a class of RNA transcripts that generally cannot encode proteins and have been demonstrated to play critical roles in regulating ferroptosis. Herein, we developed ncFO, the ncRNA–ferroptosis association database, to document the manually curated and predicted ncRNAs that are associated with ferroptosis. Collectively, ncFO contains 90 experimentally verified entries, including 46 microRNAs (miRNAs), 21 long non-coding RNAs (lncRNAs), and 17 circular RNAs (circRNAs). In addition, ncFO also incorporates two online prediction tools based on the regulation and co-expression of ncRNA and ferroptosis genes. Using default parameters, we obtained 3260 predicted entries, including 598 miRNAs and 178 lncRNAs, by regulation, as well as 2,592,661 predicted entries, including 967 miRNAs and 9632 lncRNAs, by ncRNA–ferroptosis gene co-expression in more than 8000 samples across 20 cancer types. The detailed information of each entry includes ncRNA name, disease, species, tissue, target, regulation, publication time, and PubMed identifier. ncFO also provides survival analysis and differential expression analysis for ncRNAs. In summary, ncFO offers a user-friendly platform to search and predict ferroptosis-associated ncRNAs, which might facilitate research on ferroptosis and discover potential targets for cancer treatment. ncFO can be accessed at http://www.jianglab.cn/ncFO/.

The Role Played by Ferroptosis in Osteoarthritis: Evidence Based on Iron Dyshomeostasis and Lipid Peroxidation.

Ferroptosis, a recently discovered regulated cell death modality, is characterised by iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels but can be specifically reversed by ferroptosis inhibitors. Osteoarthritis (OA), the most common degenerative joint disease, is characterised by a complex pathogenesis involving mechanical overload, increased inflammatory mediator levels, metabolic alterations, and cell senescence and death. Since iron accumulation and oxidative stress are the universal pathological features of OA, the role played by ferroptosis in OA has been extensively explored. Increasing evidence has shown that iron dyshomeostasis and lipid peroxidation are closely associated with OA pathogenesis. Therefore, in this review, we summarize recent evidence by focusing on ferroptotic mechanisms and the role played by ferroptosis in OA pathogenesis from the perspectives of clinical findings, animal models, and cell research. By summarizing recent research advances that characterize the relationship between ferroptosis and OA, we highlight avenues for further research and potential therapeutic targets.

Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis.

Acute kidney injury (AKI) is still a puzzling clinical problem; its pathophysiology is not completely understood. Up to now, an effective treatment for AKI is lacking. Ferroptosis is a novel form of regulated cell death characterized by the lethal accumulation of lipid hydroperoxides that are dependent on iron and reactive oxygen species and mitochondrial dysfunction. Recently, ferroptosis was shown to play a vital role in AKI such as ischemia-reperfusion kidney injury and folic acid-induced AKI. Melatonin (MT) is an antioxidant that regulates the sleep-wake cycle. While the therapeutic effect of melatonin on AKI has been reported, its mechanism for the treatment of renal ferroptosis remains unclear. We found that melatonin treatment significantly alleviated the serum biochemistry index and histopathological alterations in vivo AKI models induced by bilateral renal artery ischemia reperfusion and folic acid in mice. Ferroptosis induced by hypoxia and reoxygenation or erastin (Era) in mouse tubular epithelial cells (MTEC) was also rescued by melatonin treatment. RNA sequence analysis of ferroptosis-related genes showed that melatonin affects oxidative stress responses by inhibiting hypoxia and reoxygenation- (HR-) mediated downregulation of NRF2 and upregulation of Slc7a11 in MTEC. Specific knockdown of NRF2 increased the sensitivity of cells to ferroptosis, and melatonin failed to protect against ferroptosis in the HR condition. Together, our data indicate that melatonin prevents ferroptosis in AKI by acting on the NRF2/Slc7a11 axis.

Modulation of the Tumor Immune Microenvironment by Bi2 Te3 -Au/Pd-Based Theranostic Nanocatalysts Enables Efficient Cancer Therapy.

Nanozymes with multienzyme-mimicking activities have shown great potential in cancer therapy due to their ability to modulate the complex tumor microenvironment (TME). Herein, a second near-infrared (NIR-II) photothermal-nanocatalyst by decorating Bi2 Te3 nanosheets with ultrasmall Au/Pd bimetallic nanoparticles (Bi2 Te3 -Au/Pd) to reverse the immunosuppressive TME is developed. The peroxidase (POD)-like and catalase (CAT)-like activities, and glutathione (GSH) consumption capacity of Au/Pd modulates the TME by disrupting the intracellular redox homeostasis and relieving hypoxia in the TME. Notably, the amplified oxidative stress induces the accumulation of lipid hydroperoxides (LPO) for enhanced ferroptosis. Moreover, upon NIR-II photoirradiation at 1064nm, the localized heat generated by Bi2 Te3 not only directly ablates the cancer cells but also enhances the Au/Pd-mediated catalysis-mediated cancer therapy. Furthermore, both in vitro and in vivo studies confirm that the Bi2 Te3 -Au/Pd nanocatalysts (BAP NCs) can effectively suppress tumor growth by inducing immunogenic cell death (ICD), and suppressing metastasis and recurrence by the synergistic treatment. Overall, this study provides a promising theranostic strategy for effective tumor inhibition.

Oxidative Stress and Lipid Dysregulation in Lipid Droplets: A Connection to Chronic Kidney Disease Revealed in Human Kidney Cells

Chronic kidney disease (CKD), which is defined as a condition causing the gradual loss of kidney function, shows renal lipid droplet (LD) accumulation that is associated with oxidative damage. There is a possibility that an LD abnormality in quality plays a role in CKD development. This study aimed to explore the chemical composition of LDs that are induced in human kidney cells during exposure to free fatty acids as an LD source and oxidized lipoproteins as oxidative stress. The LDs were aspirated directly from cells using nanotips, followed by in-tip microextraction, and the LD lipidomic profiling was conducted using nanoelectrospray mass spectrometry. As a result, the free fatty acids increased the LD lipid content and, at the same time, changed their composition significantly. The oxidized lipoproteins caused distorted proportions of intact lipids, such as triacylglycerols (TG), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and cholesteryl esters (CE). Notably, the oxidized lipids, including the hydroperoxides of TG, PC, and PE, exhibited significant elevations in dose-dependent manners. Furthermore, the dysregulation of intact lipids was paralleled with the accumulation of lipid hydroperoxides. The present study has revealed that the oxidation of lipids and the dysregulation of the lipid metabolism coexisted in LDs in the kidney cells, which has provided a potential new target for diagnosis and new insights into CKD.