JOURNAL/nrgr/04.03/01300535-202601000-00043/figure1/v/2025-06-09T151831Z/r/image-tiff Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss. Ferroptosis has been demonstrated to be associated with retinal degenerative diseases. However, the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored. Bioinformatics and biochemical analyses in this study revealed xC - , solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model. This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway, through which cystine depletion, iron ion accumulation, and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment. We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo . Conversely, solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H 2 O 2 -induced ferroptosis of 661W cells. These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.

Heme oxygenase-1 (HO-1), which is significantly induced in response to oxidative stress, plays a crucial role in mitigating oxidative damage. However, the function of HO-1 in crayfish remains unknown. In this study, HO-1 in Procambarus clarkii (PcHO-1) was identified, and its functional domain was conserved across different species based on sequence alignment and structural prediction. Through RT-qPCR analysis, PcHO-1 showed the highest expression level in the hepatopancreas. Under the stimulation of Aeromonas hydrophila or glufosinate ammonium (GLA), the crayfish showed oxidative stress damage, whereas the expression levels of PcHO-1 were increased. Knocking down of PcHO-1 with RNA interference significantly reduced the antioxidant capacity of crayfish compared to the control group under A. hydrophila or GLA stimulation. Furthermore, the expression level of PcHO-1 increased after induction with CoPPIX, which increased the antioxidant level of crayfish and reduced the apoptosis. These findings indicated that PcHO-1 manifests the antioxidant and anti-apoptotic capacity, thereby aiding in the repairing of damage caused by A. hydrophila or GLA in P. clarkii.

Metabolic dysfunction-associated steatohepatitis (MASH) is a human health-threatening hepatic disease with limited treatment strategies. As a clinical Traditional Chinese Medicine compound for MASH, Shugan Xiaozhi (SGXZ) decoction has a definite effect, but its mechanism in treating MASH is still not very clear.

Exploring the potential mechanism of SGXZ decoction in treating MASH through multiomics and animal experimental validation.

UPLC-ESI-MS method was used to identify the main components of SGXZ decoction. Periodic acid-schiff (PAS), picrosirius red (PSR), and oil red o staining were used to assess the effect of SGXZ decoction on MCD-induced MASH mouse model. The mechanism of SGXZ decoction on MASH was analyzed using multiomics techniques. TUNEL staining, western blot (WB), immunohistochemistry (IHC), kits, transmission electron microscopy (TEM), and immunofluorescence (IF) were used to validate the mechanism of SGXZ decoction on MASH. Finally, molecular docking and molecular dynamics simulation were used to verify the targeting between key components of SGXZ decoction and important targets for intervention.

Through UPLC-ESI-MS analysis, 30 main active ingredients were obtained from SGXZ decoction. SGXZ decoction improved MASH, as evidenced by the improvement in histopathology, hepatic function indexes, lipid and fibrosis indicators. Both proteomic and transcriptomic results suggested an important role for ferroptosis in SGXZ decoction intervention in MASH, ferroptosis-related pathways were the main significant pathways obtained from these analyses. In addition, SGXZ decoction treatment reduced cell death, inflammation, and oxidative stress levels and restored impaired mitochondrial morphology in MCD-induced MASH mice. Furthermore, Mechanism experiments proved that SGXZ decoction treatment improved iron metabolism and lipid peroxidation imbalance and activated the Xc- system in MASH mice.

SGXZ decoction does have a therapeutic effect on MASH, and its mechanism may be related to its regulation of p53/ SLC7A11/GPX4 pathway to reduce ferroptosis.

Ferroptosis is a regulated form of cell death characterised by iron-dependent lipid peroxidation, a process intricately linked to cellular redox homeostasis. This form of cell death is induced by the accumulation of intracellular iron and the subsequent generation of reactive oxygen species (ROS), which leads to lipid peroxidation and ultimately cell death. Ferroptosis is distinct from traditional forms of cell death, such as apoptosis, and holds significant therapeutic potential, particularly in cancers harboring rat sarcoma virus (RAS) mutations, such as epithelial ovarian cancer (EOC). EOC is notoriously resistant to conventional therapies and is associated with a poor prognosis. In this review, we examine recent progress in the understanding of ferroptosis, with a particular focus on its redox biology and the complex regulatory networks involved. We also propose a novel classification system for ferroptosis modulators, grouping them into six categories (I, II, III, IV, V and VI) based on their mechanisms of action and their roles in modulating cellular redox status. By refining these categories, we aim to provide deeper insights into the role of ferroptosis in cancer biology, especially in EOC, and to identify potential therapeutic avenues. We propose that further investigation of ferroptosis in the context of redox biology could reveal novel biomarkers and therapeutic targets, offering promising strategies to overcome resistance mechanisms and improve clinical outcomes for patients with EOC and other treatment-resistant cancers.

The photosensitizing properties of aloe-emodin were investigated under physiological conditions using computational chemistry tools. The neutral and monoanionic species were found to coexist in a 98:2 ratio, with dissociation causing a redshift in the absorption spectrum. Aloe-emodin exhibits high two-photon absorption cross-section values within the therapeutic window and significant transition probabilities, making it an efficient two-photon photosensitizer. Excited-state dynamics analysis revealed a triplet state quantum yield of 0.51 for the neutral species and around 0.88-0.89 for the anionic species, with triplet lifetimes of 26.0 s and 0.66 s, respectively. Both species exhibit similar Type I photoreactivity, but the neutral form more effectively oxidizes biomolecules during Type III photoreactivity. Additionally, the neutral species intercalates into DNA, particularly at the AT-TA site, inducing absorption changes and structural nucleotide rearrangements. The computational results align closely with available experimental data, further confirming their reliability.

Currently, blue light irradiation is frequently encountered in daily life and is widely considered a high-risk factor for retinal damage. In particular, blue light-induced dysfunction and death of the retinal pigment epithelium (RPE) may ultimately contribute to irreversible vision impairment and even blindness. However, the underlying pathogenic mechanism and pathogenically targeted protection against blue light-induced RPE degeneration remain unclear. In this study, through sophisticated biochemical evaluation and high-throughput sequencing, the predominant pathological process during blue light-induced RPE degeneration was confirmed to be HMOX1-mediated RPE ferroptosis, which may be involved in the Nrf2-SLC7A11-HMOX1 hierarchy. Upon further knockdown of HMOX1 with si-HMOX1 or the HMOX1 inhibitor zinc protoporphyrin (ZnPP), specific inhibition of HMOX1 overexpression significantly suppressed RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and visual function. These results highlighted that HMOX1-mediated ferroptosis might be a potential target for protection against blue light-induced damage to RPE cells.

Iron-induced lipid peroxidation of phosphatidylethanolamine (PE) species is a key driver of ferroptosis in retinal pigment epithelial (RPE) cells, a process closely associated with age-related macular degeneration (AMD). The previous studies have demonstrated that induced retinal pigment epithelial (iRPE) cells generated by transcription factor-mediated reprogramming exhibit superior therapeutic efficacy in treating AMD. In this study, it is found that these iRPE cells are resistant to ferroptosis and further identified phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1) as a critical regulator underlying ferroptosis resistance. Mechanistically, PHOSPHO1 inhibits ferroptosis through two distinct mechanisms. First, it reduces PE levels in the endoplasmic reticulum, thereby limiting PE-derived lipid peroxidation. Second, it suppresses autophagy and ferritinophagy, leading to a reduction in intracellular free iron accumulation. Experiments using an in vivo rat model confirm that PHOSPHO1 effectively protects RPE cells from ferroptotic damage. These findings highlight PHOSPHO1 as a potential therapeutic target for AMD, providing insights into novel ferroptosis-based intervention strategies.

Metabolic dysfunction-associated steatohepatitis (MASH) can progress to liver cirrhosis, increasing mortality risk. The study investigates the role of ferroptosis-an inflammatory cell death mechanism-in MASH and evaluates the therapeutic effects of mitoglitazone and proanthocyanidin in targeting ferroptosis to mitigate MASH progression. Forty male albino mice were divided into five groups (n = 8): normal control (NC) fed a standard chow diet and given 2% DMSO; MASH group was maintained on MASH protocol (high fructose-high fat diet); mitoglitazone (Mito) group was kept on MASH protocol and given Mito (10 mg/kg/day); proanthocyanidin (Pro) group was kept on MASH protocol and given Pro (150 mg/kg/day); Mito + Pro co-treated group was given Mito and Pro parallel with MASH protocol, all treatments for 12 weeks. MASH induction significantly (p < 0.001) increased liver weight, liver index, serum liver enzymes (ALT & AST), serum glucose, insulin, insulin resistance (HOMA-IR), lipid profile (total cholesterol, triglycerides, LDL-C), ferroptosis biomarkers (total iron, soluble transferrin receptor-1 (sTfR1), and expression of liver acyl-CoA synthetase long-chain family member 4 (ACSL4) with diffused macrovesicular severe steatosis, and inflammatory cells infiltration in liver tissues compared to NC. However, HDL-cholesterol, ferroptosis biomarkers (liver glutathione peroxidase X4 (GPX4), and total glutathione peroxidase (GPX) activities and glutathione (GSH) content) were reduced significantly (p < 0.001) in MASH group compared to NC. On the other hand, Mito, Pro, and their combination significantly improved ferroptotic biomarkers (GSH, GPX4, sTFR1, and total iron and ACSL-4 gene expression), glucose homeostasis, lipid profile, liver enzymes, and histology compared to MASH group. Combining the insulin-sensitizing properties with targeting of ferroptosis, by the co-treatment with mitoglitazone (MSDC-0160) and proanthocyanidin, could be beneficial in inhibition of lipogenesis with retardation of MASH development in mice.

The main challenge in dissecting the cells and pathways involved in the pathogenesis of age-related macular degeneration (AMD) is the highly heterogeneous and dynamic nature of the retinal microenvironment. This study aimed to describe the comprehensive landscape of the dry AMD (dAMD) model and identify the key cell cluster contributing to dAMD. We identified a subset of Müller cells that express high levels of Sox2, which play crucial roles in homeostasis and neuroprotection in both mouse models of AMD and patients with dAMD. Additionally, the number of Sox2+ Müller cells decreased significantly during the progression of AMD, indicating these cells were damaged and underwent cell death. Interestingly, ferroptosis and apoptosis were identified as contributors to the damage of Sox2+ Müller cells. Our findings are potentially valuable not only for advancing the current understanding of dAMD progression but also for the development of treatment strategies through the protection of Müller cells.

Background/Objectives: Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness in elderly individuals aged over 50 years old. Oxidative stress plays a crucial role in the etiopathogenesis of multifactorial AMD disease. The phospholipid bilayer EVs derived from the culture-conditioned medium of human induced pluripotent stem cell (hiPSC) differentiated retinal organoids aid in cell-to-cell communication, signaling, and extracellular matrix remodeling. The goal of the current study is to establish and evaluate the encapsulation of a hydrophobic compound, cannabidiol (CBD), into retinal organoid-derived extracellular vesicles (EVs) for potential therapeutic use in AMD. Methods: hiPSC-derived retinal organoid EVs were encapsulated with CBD via sonication (CBD-EVs), and structural features were elucidated using atomic force microscopy, nanoparticle tracking analysis, and small/microRNA (miRNA) sequencing. ARPE-19 cells and oxidative-stressed (H2O2) ARPE-19 cells treated with CBD-EVs were assessed for cytotoxicity, apoptosis (MTT assay), reactive oxygen species (DCFDA), and antioxidant proteins (immunohistochemistry and Western blot). Results: Distinct miRNA cargo were identified in early and late retinal organoid-derived EVs, implicating their roles in retinal development, differentiation, and functionality. The therapeutic effects of CBD-loaded EVs on oxidative-stressed ARPE-19 cells showed greater viability, decreased ROS production, downregulated expression of inflammation- and apoptosis-related proteins, and upregulated expression of antioxidants by Western blot and immunocytochemistry. Conclusions: miRNAs are both prognostic and predictive biomarkers and can be a target for developing therapy since they regulate RPE physiology and diseases. Our findings indicate that CBD-EVs could potentially alleviate the course of AMD by activating the targeted proteins linked to the adenosine monophosphate kinase (AMPK) pathway. Implicating the use of CBD-EVs represents a novel frontline to promote long-term abstinence from drugs and pharmacotherapy development in treating AMD.

The mechanism of age-related macular degeneration (AMD) is a complex illness that is not fully understood. Therefore, the aim of this study was to investigate the expression patterns of miR-6837-3p in retinal epithelial cells.

H2O2 was used to treat ARPE-19 cells for 2, 4 and 6 h to mimic the in vivo environment of AMD. MiR inhibitors and mimics were used to inhibit or overexpress miR-6837-3p in H2O2-treated ARPE-19 cells, respectively. Then, CCK8 assay, flow cytometry, and wound healing assays were conducted to assess the effects of miR-6837-3p on the behaviors of ARPE-19 cells, including cell growth, apoptosis, cycle progression, and migration. Finally, microRNA database prediction and luciferase reporter assays were used to demonstrate that miR-6837-3p targets the downstream gene E2F6.

H2O2 induced a decrease in cell viability and an increase in ROS levels in a time-dependent manner. Additionally, overexpression of miR-6837-3p increased cell viability and suppressed apoptosis in ARPE-19 cells treated with H2O2. Meanwhile, increased miR-6837-3p promoted cell cycle progression and cell migration of ARPE-19 cells. Finally, miR-6837-3p exerted anti-apoptosis and anti-oxidative stress effects by inhibiting the expression of E2F6 in ARPE-19 cells.

The MiR-6837-3p/E2F6 axis might be a target for the treatment of AMD to improve ARPE-19 cell function.

This study aims to elucidate the therapeutic effects and underlying mechanisms of exosomes derived from Heme oxygenase 1 (HO-1)-overexpressing human umbilical cord mesenchymal stem cells (ExoHO-1) in a subarachnoid hemorrhage (SAH) mouse model.

In this study, exosomes were identified using Western blotting, particle analysis, and transmission electron microscopy. The effect of ExoHO-1 and ExoCtrl on the neurological function of SAH mice was assessed using the Garcia scoring system, Beam balance, Rotarod test, and Morris water maze test. Neuronal apoptosis and survival were evaluated through TUNEL and Nissl staining. Levels of oxidative and endoplasmic reticulum stress were measured via immunofluorescence, Western blotting, DHE staining, enzyme-linked immunosorbent assay, and commercial kits.

HO-1-overexpressing human umbilical cord mesenchymal stem cells encapsulated HO-1 into their exosomes. ExoHO-1 significantly enhanced both short-term and long-term neurological function protection. By reducing the activation of the PERK/CHOP/Caspase12 pathway and decreasing oxidative stress levels, ExoHO-1 effectively inhibited neuronal apoptosis in the ipsilateral temporal cortex.

ExoHO-1 enhances the therapeutic efficacy of exosomes in SAH mice by countering neuronal apoptosis, primarily through the suppression of oxidative and endoplasmic reticulum stress.

Ferroptosis, a novel form of regulated cell death (RCD), has emerged as a promising therapeutic strategy for cancer treatment. While gold nanoparticles (AuNPs) are known to induce cell death and ferroptosis in combination with certain antibiotics, the mechanisms underlying ferroptosis in microorganisms remain poorly understood. This study aimed to investigate whether AuNPs induce ferroptosis-like cell death in the eukaryotic microbe Saccharomyces cerevisiae. Our findings revealed that AuNPs significantly reduced cell viability in S. cerevisiae, suggesting their ability to trigger cell death. Ferroptosis-related precursors, including intracellular iron overload and depletion of glutathione (GSH), were observed, leading to the inactivation of glutathione peroxidase (GPx). These changes were associated with the accumulation of reactive oxygen species (ROS) and lipid peroxidation, which amplified oxidative stress within the cells. Elevated ROS levels and lipid peroxidation further resulted in membrane rupture and the formation of 8-hydroxydeoxyguanosine, indicating DNA damage. Mitochondrial dysfunction, a hallmark of ferroptosis, was also evident. AuNP treatment caused mitochondrial membrane potential hyperpolarization and a reduction in mitochondrial membrane density. Unlike previously characterized forms of RCD, ferroptosis-like death in S. cerevisiae did not involve chromatin condensation, DNA fragmentation, or metacaspase activation. Finally, ferroptosis-like characteristics were confirmed using Liperfluo, a lipid ROS-specific probe. In conclusion, this study demonstrated that AuNPs can induce ferroptosis-like cell death in S. cerevisiae. These findings highlight the potential of AuNPs as antifungal agents and contribute to the broader understanding of ferroptosis in eukaryotic microbes.

Cells undergoing regulated necrosis systemically communicate with the immune system via the release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.

Genome-wide association studies (GWASs) have identified more than 1000 loci where genetic variants correlate with kidney function. However, the specific genes, cell types, and mechanisms influenced by these genetic variants remain largely uncharted. Here, we identified glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) on chromosome 15 as affected by GWAS variants by analyzing human kidney gene expression and methylation information. Both CHAC1 RNA and protein were expressed in the loop of Henle region in mouse and human kidneys, and CHAC1 expression was higher in patients carrying disease risk variants. Using CRISPR technology, we created mice with a single functional copy of the Chac1 gene (Chac1+/-) that displayed no baseline phenotypic alterations in kidney structure or function. These mice demonstrated resilience to kidney disease in multiple models, including folic acid-induced nephropathy, adenine-induced chronic kidney disease, and uninephrectomy-streptozotocin-induced diabetic nephropathy. We further showed that CHAC1 plays a critical role in degrading the cellular antioxidant glutathione. Tubule cells isolated from Chac1+/- mice showed increased glutathione, decreased lipid peroxidation, improved cell viability, and protection against ferroptosis. Expression of ferroptosis-associated genes was also lower in mice with only one copy of Chac1. Higher CHAC1 protein also correlated with ferroptosis-related protein abundance in kidney biopsies from patients with kidney disease. This study positions CHAC1 as an important mediator of kidney disease that influences glutathione concentrations and ferroptosis, suggesting potential avenues to explore for the treatment of kidney diseases.

Globally, drug-induced hepatotoxicity or drug-induced liver injury (DILI) is a serious clinical concern. Knowing the processes and patterns of cell death is essential for finding new therapeutic targets since there are not many alternatives to therapy for severe liver lesions. Excessive lipid peroxidation is a hallmark of ferroptosis, an iron-reliant non-apoptotic cell death linked to various liver pathologies. When iron is pathogenic, concomitant inflammation may exacerbate iron-mediated liver injury, and the hepatocyte necrosis that results is a key element in the fibrogenic response. The idea that dysregulated metabolic pathways and compromised iron homeostasis contribute to the development of liver injury by ferroptosis is being supported by new data. Various ferroptosis-linked genes and pathways have been linked to liver injury, although the molecular processes behind ferroptosis's pathogenicity are not well known. Here, we delve into the features of ferroptosis, the processes governing ferroptosis, and our current knowledge of iron metabolism. We also provide an overview of ferroptosis's involvement in the pathophysiology of liver injury, particularly DILI. Lastly, the therapeutic possibilities of ferroptosis targeting for liver injury management have been provided. Natural products, nanoparticles (NPs), mesenchymal stem cell (MSC), and their exosomes have attracted increasing attention among such therapeutics.

Iron homeostasis plays an important role in maintaining cellular homeostasis; however, excessive iron can promote the production of reactive oxygen species (ROS). Ferroptosis is iron-dependent programmed cell death that is characterized by excessive iron accumulation, elevated lipid peroxides, and the overproduction of ROS. The maintenance of iron homeostasis is contingent upon the activity of the transferrin receptor (TfR), ferritin (Ft), and ferroportin (FPn). In the retina, iron accumulation and lipid peroxidation can contribute to the development of age-related macular degeneration (AMD). This phenomenon can be explained by the occurrence of the Fenton reaction, in which the interaction between divalent iron and hydrogen peroxide leads to the generation of highly reactive hydroxyl radicals. The hydroxyl radicals exhibit a propensity to attack proteins, lipids, nucleic acids, and carbohydrates, thereby instigating oxidative damage and promoting lipid peroxidation. Ultimately, these processes culminate in cell death and retinal degeneration. In this context, a comprehensive understanding of the exact mechanisms underlying ferroptosis may hold significant importance for developing therapeutic interventions. This review summarizes recent findings on iron metabolism, cellular ferroptosis, and lipid metabolism in the aging retina. We also introduce developments in the therapeutic strategies using iron chelating agents. Further refinements of these knowledges would deepen our comprehension of the pathophysiology of AMD and advance the clinical management of degenerative retinopathy. A comprehensive search strategy was employed to identify relevant studies on the role of ferroptosis in AMD. We performed systematic searches of the PubMed and Web of Science electronic databases from inception to the current date. The keywords used in the search included "ferroptosis", "AMD", "age-related macular degeneration", "iron metabolism", "oxidative stress", and "ferroptosis pathways". Peer-reviewed articles, including original research, reviews, meta-analyses, and clinical studies, were included in this paper, with a focus on the molecular mechanisms of ferroptosis in AMDs. Studies not directly related to ferroptosis, iron metabolism, or oxidative stress in the context of AMD were excluded. Furthermore, articles that lacked sufficient data or were not peer-reviewed (e.g., conference abstracts, editorials, or opinion pieces) were not considered.

Age-related macular degeneration (AMD) is associated with chronic inflammation of the retinal pigment epithelium (RPE) and elevated cytokines including TNFα, TGF-β, IL-6, and IL-1β. As a metabolic intermediary supporting aerobic glycolysis in the adjacent photoreceptors, the RPE's metabolic responses to inflammation and the optimal methods to study cytokine-driven metabolic programming remain unclear. We performed a rigorous comparison of ARPE-19 cells and rat eyecup metabolomes, revealing key distinctions. Rat eyecups exhibit higher levels of lactate and palmitate but depleted glutathione and high-energy nucleotides. Conversely, ARPE-19 cells are enriched with high-energy currency metabolites and the membrane phospholipid precursors phosphocholine and inositol. Both models showed contrasting responses to individual cytokines: ARPE-19 cells were more sensitive to TNFα, while eyecups responded more strongly to TGF-β2. Notably, a combined cytokine cocktail elicited stronger metabolic effects on ARPE-19 cells, more potently impacting both metabolite abundance (41 vs. 29) and glucose carbon flux (29 vs. 5), and influencing key RPE metabolites such as alanine, glycine, aspartate, proline, citrate, α-ketoglutarate, and palmitate. Overall, these findings position ARPE-19 cells as a more responsive platform for studying inflammatory cytokine effects on RPE metabolism and reveal critical RPE metabolites which may be linked with AMD pathogenesis.

Considering that the fetal redox homeostasis is a key factor for normal prenatal development, this study researched the effects of maternal thrombophilia on fetal redox homeostasis by assessing the redox profile of amniotic fluid cells and amniotic fluid during the second trimester of pregnancy. Concentration of redox biomarkers (superoxide anion, O2.-; hydrogen peroxide, H2O2; nitric oxide, NO; peroxynitrite, ONOO-; lipid peroxides, LPO, micronuclei, reduced glutathione, GSH; oxidized glutathione, GSSG) were assayed in the amniotic fluid cells and amniotic fluid of healthy pregnant women and pregnant women with thrombophilia gestational age from 16 to 18 weeks. Results of this study indicate that pregnant women with thrombophilia have significantly higher concentrations of O2.-, NO, ONOO-, and LPO but lower concentrations of H2O2, GSH, and GSSG in the amniotic fluid cells, as well as a higher concentration of GSSG in the amniotic fluid. No difference is shown in concentration of O2.-, H2O2, NO, ONOO-, LPO, and GSH in the amniotic fluid, as well as in frequency of micronuclei in the amniotic fluid cells among investigated groups of pregnant women. The present study provides the first evidence that babies born to mothers with thrombophilia in the second trimester of intrauterine life experience intense oxidative stress characterized by overproduction of O2.-, NO, ONOO-, and LPO, as well as GSH depletion.

Background/Objectives: The exposome, encompassing all environmental influences on health, plays a pivotal role in oxidative stress-related diseases. Negative air ions (NAIs), generated via cold atmospheric plasma (CAP), have been proposed as potential modulators of oxidative resilience. This study aims to investigate the metabolic adaptations induced by prolonged exposure to an NAI-enriched environment in mice, focusing on its effects in oxidative stress markers and energy metabolism in liver and blood. Methods: Twenty male C57BL/6J mice were divided into four groups: two experimental groups exposed to NAI-enriched air generated by an Air Cold Atmospheric Plasma-Nanoparticle Removal (aCAP-NR) device for either 18 days (short-term, ST) or 28 days (long-term, LT), and two control groups without exposure. Targeted metabolomics was performed in whole blood and liver using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Statistical and pathway analyses were conducted to assess metabolic alterations. Results: Metabolic profiling revealed significant shifts in oxidative stress-related pathways, including enhanced glutathione metabolism, reduced lipid peroxidation, and modulation of purine metabolism. Short-term exposure led to increased mitochondrial efficiency and energy homeostasis, while long-term exposure induced adaptive metabolic reprogramming, with higher inosine levels suggesting enhanced antioxidant and anti-inflammatory responses. No adverse effects on systemic or hepatic health markers were observed. Conclusions: NAI exposure via aCAP-NR elicits a hormetic response, enhancing metabolic efficiency and resilience to oxidative stress. These findings suggest that controlled environmental enrichment with NAIs may serve as a novel non-invasive strategy for mitigating oxidative damage and improving metabolic health, as hormetic adaptative capacity and resilience to oxidative stress, warranting further translational research.

Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.

Aims: Itaconate (IA) is synthesized in the citric acid cycle via cis-aconitate decarboxylase (ACOD1); however, its biological significance in cancer remains incompletely understood. In previous studies, 4-octyl itaconate (OI) was used as a membrane-permeable form of IA, but little detailed verification of the difference in biological activities between IA and OI exists. Here, we investigated the direct effects of IA and OI on melanoma. Results: The proliferation of melanoma cells treated with OI was significantly suppressed in vitro, and our transcriptomic analysis revealed drastic changes in the expression of glutathione metabolism-related genes in OI-treated cells. Indeed, OI treatment decreased intracellular glutathione levels, followed by increased production of reactive oxygen species and expression of γH2AX, a marker of DNA damage, and β-galactosidase, a marker of cellular senescence. We further showed that the mitochondrial respiratory capacity in B16 cells was significantly decreased by OI treatment. OI administration also suppressed the growth of B16 tumor transplants in vivo, and the expression of γH2AX was increased in tumor tissues of OI-treated mice. In addition, minimal effects of OI treatment were observed in melanocytes and normal tissues. We also proved that not only exogenous IA, which enters intracellularly, but also endogenous IA has little effect on melanoma proliferation activity, via an investigation using Acod1-overexpressing transfectants and Acod1-deficient mice. Conclusion: This work revealed that OI disrupts the antioxidant system via the collapse of glutathione metabolism and inhibits cancer cell proliferation. Antioxid. Redox Signal. 42, 547-565.

This review highlights how a Ir(III) and Ru(II) coordination complexes can change theirs cytotoxic activity by interacting with a biomolecules such as deoxyribonucleic acid (DNA), human albumins (HSA), nicotinamide adenine dinucleotide (NADH), and glutathione (GSH). We have selected biomolecules (DNA, NADH, GSH, and HSA) based on their significant biological roles and importance in cellular processes. Moreover, this review may provide useful information for the development of new half-sandwich Ir(III) and Ru(II) complexes with desired properties and relevant biological activities. Additionally, the examples discussed here may help us better understand what happens to a metal-based drug once it enters the body.

Ferroptosis, a form of iron-dependent cell death, plays a pivotal role in age-related diseases; yet, its impact on cellular senescence and healthspan in mammals remains largely unexplored. This study identifies ferroptosis as a key regulator of cellular senescence, showing that its inhibition can significantly delay aging and extend healthspan across multiple species. During cellular senescence, ferroptosis is progressively exacerbated, marked by increased lipid peroxidation, oxidative stress, and diminished glutathione peroxidase 4 (GPX4) levels. Ferroptosis inducers such as Erastin and RSL3 accelerate senescence; while, inhibitors such as liproxstatin-1 (Lip-1) and ferrostatin-1 (Fer-1) effectively mitigate both chemically and replicatively induced senescence. In vivo, Fer-1 extends lifespan and healthspan in Caenorhabditis elegans, enhances motor function, preserves tissue integrity, and mitigates cognitive decline in both prematurely and naturally aged mice. These effects are attributed to Fer-1's upregulation of GPX4 and inhibition of ferroptosis. Notably, long-term Fer-1 treatment (over 6 months) does not adversely affect body weight or induce aging-related tissue damage but rejuvenates hematological parameters. These findings establish ferroptosis as a critical player in aging dynamics and highlight its inhibition as a promising strategy to extend healthspan and lifespan, providing valuable insights for translational approaches to combat aging and age-related decline.

Ferroptosis denotes a distinct form of controlled cell death marked by substantial iron buildup and significant lipid peroxidation, playing a crucial role in several disease processes linked to cell death. Given the liver's essential functions in iron and lipid metabolism and its vulnerability to oxidative damage, more research has investigated the correlation between ferroptosis and numerous hepatic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). NAFLD has arisen as a worldwide public health concern due to elevated morbidity and high death rates. The pathogenesis of MASLD remains incompletely elucidated. Recent data suggests that ferroptosis is crucial in the pathophysiology of MASLD; nevertheless, the specific processes by which ferroptosis influences MASLD remain unclear. The present review summarizes the molecular processes of ferroptosis and its intricate regulatory networks, outlines the differing impacts of ferroptosis at different stages of MASLD, and examines possible approaches targeting ferroptosis for the therapy of MASLD, suggesting a novel approach for its management.

Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.

Diabetic macular edema (DME) is the most common cause of vision loss in people with diabetes. Tight junction disruption of the retinal pigment epithelium (RPE) cells has been reported to induce DME development. SMAD-specific E3 ubiquitin protein ligase (SMURF) 1 was associated with the tight junctions of cells. However, the mechanism of SMURF1 in the DME process remains unclear.

To investigate the role of SMURF1 in RPE cell tight junction during DME.

ARPE-19 cells treated with high glucose (HG) and desferrioxamine mesylate (DFX) for establishment of the DME cell model. DME mice models were constructed by streptozotocin induction. The trans-epithelial electrical resistance and permeability of RPE cells were analyzed. The expressions of tight junction-related and autophagy-related proteins were determined. The interaction between insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and SMURF1 mRNA was verified by RNA immunoprecipitation (RIP). SMURF1 N6-methyladenosine (m6A) level was detected by methylated RIP.

SMURF1 and vascular endothelial growth factor (VEGF) were upregulated in DME. SMURF1 knockdown reduced HG/DFX-induced autophagy, which protected RPE cell tight junctions and ameliorated retinal damage in DME mice. SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor (WIF) 1 ubiquitination and degradation. IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.

M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation, which activated autophagy to inhibit RPE cell tight junctions, ultimately promoting DME progression.

Ferroptosis is a non-apoptotic cell death mechanism driven by reactive oxygen species (ROS) and iron. Its significance in inflammatory arthritis is well-established, but its role in rheumatoid arthritis (RA) remains uncertain. This study aimed to clarify the mechanisms through which curcumin-mediated photodynamic therapy (CUR-PDT) triggers ferroptosis in RA fibroblast-like synoviocytes (FLSs).

In vivo studies using a collagen-induced arthritis (CIA) rat model evaluated CUR-PDT effects on joint edema, synovial inflammation, and fibrosis through paw volume measurements and H&E and Masson's trichrome staining. The expression of Nrf2, xCT, and GPX4 in FLSs was assessed via ELISA and immunohistochemistry. In vitro, MH7A cells treated with TNF-α were analyzed for viability, proliferation, invasion, and migration through various assays. Mitochondrial potential and morphology were examined using JC-1 staining and transmission electron microscopy (TEM). Ferroptosis biomarkers, including ROS, malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and Fe2+ levels, were measured. Nrf2, xCT, and GPX4 levels were quantified with RT-qPCR, Western blot, and immunofluorescence. Small interfering RNA (siRNA) was employed to knock down Nrf2 to validate the effect of CUR-PDT on ferroptosis in RA-FLS.

The CUR-PDT therapy markedly reduced joint inflammation and collagen deposition in the synovial tissue of CIA rats. It effectively alleviated both inflammation and hyperplasia. Moreover, this therapy facilitated ferroptosis within the synovial tissue. In vitro analyses indicated that CUR-PDT diminished the proliferation and viability of FLSs, resulting in increased ROS levels in the cells. This cascade initiated ferroptosis, as evidenced by decreased glutathione, heightened iron concentrations, mitochondrial shrinkage, and reduced mitochondrial membrane potential. Crucially, the expression of xCT and GPX4 was significantly lowered. Interestingly, knocking down the Nrf2 gene amplified this effect, leading to an even greater reduction in xCT and GPX4 expression. In this context, RA-FLSs exhibited more pronounced ferroptotic traits, including diminished proliferation, invasion, and migration.

This study elucidated a mechanism by which CUR-PDT triggers ferroptosis in FLSs through the downregulation of the Nrf2-xCT-GPX4 signaling cascade, thereby effectively hindering the progression of RA and emphasizing the importance of targeting Nrf2 in disease advancement.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in the aging population. Evidence showing the presence of cellular senescence in retinal pigment epithelium (RPE) of patients with AMD is growing. Senescent RPE play a pivotal role in its pathogenesis. The senescent RPE suffers from structural and functional alterations and disruption of the surrounding microenvironment due to the development of the senescence-associated secretory phenotype, which contributes to metabolic dysfunctions and inflammatory responses in the retina. Senotherapeutics, including senolytics, senomorphics and others, are novel treatments targeting senescent cells and are promising treatments for AMD. As senotherapeutic targets are being developed, it is promising that the burden of AMD could be decreased.

Ulcerative colitis (UC) is a chronic and recurrent gastrointestinal disease that affects millions of humans worldwide and imposes a huge social and economic burden. It is necessary to find safe and efficient drugs for preventing and treating UC. The aim of this study was to determine whether ganoderic acid (GA), the main bioactive components of Ganoderma lucidum, has preventive and therapeutic effect on UC in a dextran sulfate sodium (DSS)-induced UC mouse model. Our experimental results showed that GA significantly ameliorated the body weight loss and disease activity index (DAI) of UC mice. GA significantly restored 11% of the colon length and 69% of the spleen index compared to UC mice. GA significantly decreased the intestinal inflammatory response and improved the barrier function of the intestine by upregulating the tight junction proteins Zonula occludens-1 (ZO-1), occludin and claudin-1. A co-housing experiment showed that gut microbiota accounted for the therapeutic activity of GA on UC, which was confirmed by fecal microbiota transplantation from GA-treated mice to the UC mice. Furthermore, 16S rDNA high-throughput sequencing of fecal bacteria showed that GA significantly enriched the abundance of Lactobacillus, Oscillospira, Odoribacter and Ruminococcus, which were positively correlated with colon length. Furthermore, this study found the functional metabolites, including Indole-3-acetaldehyde (IAAld), Glutamine (Gln) and Glutathione (GSH), reduced barrier damage in the Caco-2 cell model. In conclusion, this study suggests that GA could ameliorate UC by improving intestinal barrier function via modulating gut microbiota and associated metabolites.

In recent 10 years, ferroptosis has become a hot research direction in the scientific research community as a new way of cell death. Iron toxicity accumulation and lipotoxicity are unique features. Several studies have found that ferroptosis is involved in the regulation of the hepatic microenvironment and various hepatic metabolisms, thereby mediating the progression of related liver diseases. For example, NRF2 and FSP1, as important regulatory proteins of ferroptosis, are involved in the development of liver tumors and liver failure. In this manuscript, we present the mechanisms involved in ferroptosis, the concern of ferroptosis with the liver microenvironment and the progression of ferroptosis in various liver diseases. In addition, we summarize recent clinical advances in targeted ferroptosis therapy for related diseases. We expect that this manuscript can provide a new perspective for clinical treatment of related diseases.

Nanozymes offer diverse therapeutic potentials for cancer treatment which is dependent on the development of nanomaterials. Quasi-metal-organic framework is a class of metal-organic framework-derived nanomaterials with a transition state from metal-organic frameworks towards metal oxide featuring porous structure and high activity. Herein an iron-based quasi-metal-organic framework nanozyme Q-MIL-53(Fe) is reported via a controlled deligandation strategy, exhibiting enhanced peroxidase-/catalase-mimic activity and glutathione depletion capacity, whose underlying mechanisms are studied via density functional theory calculations. Q-MIL-53(Fe) demonstrates biocompatibility and superior antitumor efficacy compared to pristine MIL-53(Fe). It can activate antitumor immune response by inducing ferroptosis and immunogenic cell death, promoting dendritic cell maturation and T lymphocytes infiltration. Furthermore, a combination of Q-MIL-53(Fe) and programmed cell death protein 1 antibody amplifies cancer immunotherapy. This study validates the antitumor activity of quasi-metal-organic frameworks and its immunotherapy induction potential. It would broaden the application of quasi-metal-organic frameworks and open avenues for developing antitumor nanozymes.

Nanoplastics and plasticizers are prevalent in activated sludge and pose a potential threat to microbial communities in wastewater treatment systems. However, studies on the effects of nanoplastics and plasticizers on the interaction mechanisms and metabolic functions of microbial communities in activated sludge systems are still scarce. In this study, the responses of microbial interactions and metabolic functions to PVC nanoplastics (PVCNPs) and bis(2-ethylhexyl) phthalate (DEHP) in activated sludge were investigated via a combination of amplicon sequencing, metagenome sequencing, and metabolic modeling. The results revealed that DEHP had a significant effect on the microbial community under short-term exposure. DEHP contamination may increase vitamin B12 producers to enhance species collaboration in communities. Furthermore, community metabolic modeling revealed that DEHP-degrading bacteria could promote positive interactions among community members. The increased metabolic exchange flux of siderophores and glutathione in microbial communities under PVCNPs and DEHP contamination implied that microbial communities may maintain iron homeostasis in response to PVCNPs and DEHP contamination through interspecies collaboration. However, more data are needed to further validate these results. This study provides vital insights into the response mechanisms of microbial interactions to nanoplastic and plasticizer contamination in activated sludge systems.

Cancer remains one of the leading causes of the death of individuals globally. Conventional treatment techniques like chemotherapy and radiation often suffer various drawbacks like toxicity and drug resistance. The study of cell death has been predominantly focused on classical forms like apoptosis, but the role of metal ions in governing controlled cell death is a fascinating and less explored area. Metal-mediated controlled cell death is a process where metal triggers cell death via a unique mechanism. Nanomaterial-based strategies have gained attention for their ability to deliver precise therapeutic agents while also triggering Regulated Cell Death (RCD) mechanisms in cancer cells. The recently discovered metal-mediated controlled cell death techniques like cuproptosis and ferroptosis can be used in cancer treatment as they can be used selectively for the treatment of drug-resistant cancer. Nano material-based delivery system can also be used for the precise delivery of the drug to the targeted sites. In this review, we have given some idea about the mechanism of metal-mediated controlled cell death techniques (ferroptosis and cuproptosis) and how we can initiate controlled cell deaths using nanomaterials for cancer treatment.

Resistance to senescence in retinal pigment epithelial (RPE) cells can delay the progression of age-related macular degeneration (AMD). However, the mechanisms underlying RPE cell senescence remain inadequately understood, and effective therapeutic strategies are lacking. While astragaloside IV (Ast) has demonstrated anti-aging properties, its specific effects on RPE cell senescence and potential mechanisms are not yet fully clarified.

This study aimed to explore the impacts of Ast on RPE cell senescence and to uncover the molecular mechanisms involved.

The therapeutic efficacy of Ast was assessed using sodium iodate (NaIO3)-induced adult retinal pigment epithelial cell line 19 (ARPE-19) cell models and an AMD mouse model. To investigate the mechanisms by which Ast mitigated RPE cell senescence, RNA sequencing (RNA-seq), drug affinity responsive target stability-mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), reverse transcription quantitative PCR (RT-qPCR), as well as western blotting were conducted.

Ast significantly inhibited NaIO3-treated ARPE-19 cell senescence and protected against NaIO3-induced AMD in mice. RNA-seq analysis revealed that Ast significantly attenuated inflammation-related signaling pathways and reduced the mRNA levels of interleukin-1 beta (IL-1β). Specifically, Ast decreased the stability of IL-1β mRNA while enhancing its N6-methyladenosine (m6A) methylation. Furthermore, Ast directly interacted with fat mass and obesity-associated protein (FTO). Knockdown or pharmacological inhibition of FTO mitigated the senescence and IL-1β expression in NaIO3-treated ARPE-19 cells. FTO was essential for Ast to inhibit cellular senescence and IL-1β expression. Additionally, inhibition or knockdown of FTO conferred also provided resistance to AMD in the murine model.

Our results indicated that Ast significantly attenuated RPE cell senescence and showed anti-AMD properties. FTO was demonstrated to be a promising therapeutic target for AMD treatment. These findings may provide a deeper understanding of the molecular mechanisms underlying RPE cell senescence in AMD and offer potential strategies for its prevention and management.