Identification of disulfidptosis- and ferroptosis-related transcripts in periodontitis by bioinformatics analysis and experimental validation.

Background: Disulfidptosis and ferroptosis are forms of programmed cell death that may be associated with the pathogenesis of periodontitis. Our study developed periodontitis-associated biomarkers combining disulfidptosis and ferroptosis, which provides a new perspective on the pathogenesis of periodontitis. Methods: Firstly, we obtained the periodontitis dataset from public databases and found disulfidptosis- and ferroptosis-related differentially expressed transcripts based on the disulfidptosis and ferroptosis transcript sets. After that, transcripts that are tissue biomarkers for periodontitis were found using three machine learning methods. We also generated transcript subclusters from two periodontitis microarray datasets: GSE16134 and GSE23586. Furthermore, three transcripts with the best classification efficiency were further screened. Their expression and classification efficacy were validated using qRT-PCR. Finally, periodontal clinical indicators of 32 clinical patients were collected, and the correlation between three transcripts above and periodontal clinical indicators was analyzed. Results: We identified six transcripts that are tissue biomarkers for periodontitis, the top three transcripts with the best classification, and delineated two expression patterns in periodontitis. Conclusions: Our study found that disulfidptosis and ferroptosis were associated with immune responses and may involve periodontitis genesis.

Ferroptosis: a novel strategy to overcome chemoresistance in gynecological malignancies.

Ferroptosis is an iron-dependent form of cell death, distinct from apoptosis, necrosis, and autophagy, and is characterized by altered iron homeostasis, reduced defense against oxidative stress, and increased lipid peroxidation. Extensive research has demonstrated that ferroptosis plays a crucial role in the treatment of gynecological malignancies, offering new strategies for cancer prevention and therapy. However, chemotherapy resistance poses an urgent challenge, significantly hindering therapeutic efficacy. Increasing evidence suggests that inducing ferroptosis can reverse tumor resistance to chemotherapy. This article reviews the mechanisms of ferroptosis and discusses its potential in reversing chemotherapy resistance in gynecological cancers. We summarized three critical pathways in regulating ferroptosis: the regulation of glutathione peroxidase 4 (GPX4), iron metabolism, and lipid peroxidation pathways, considering their prospects and challenges as strategies to reverse chemotherapy resistance. These studies provide a fresh perspective for future cancer treatment modalities.

Ferroptosis as an emerging target in sickle cell disease.

Sickle cell disease (SCD) is an inherited hemoglobin disorder marked by red blood cell sickling, resulting in severe anemia, painful episodes, extensive organ damage, and shortened life expectancy. In SCD, increased iron levels can trigger ferroptosis, a specific type of cell death characterized by reactive oxygen species (ROS) and lipid peroxide accumulation, leading to damage and organ impairments. The intricate interplay between iron, ferroptosis, inflammation, and oxidative stress in SCD underscores the necessity of thoroughly understanding these processes for the development of innovative therapeutic strategies. This review highlights the importance of balancing the complex interactions among various factors and exploitation of the knowledge in developing novel therapeutics for this devastating disease.

Targeting ferroptosis: a new therapeutic opportunity for kidney diseases.

Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and is characterized by the accumulation of lipid peroxides to lethal levels. Ferroptosis involves multiple pathways including redox balance, iron regulation, mitochondrial function, and amino acid, lipid, and glycometabolism. Furthermore, various disease-related signaling pathways also play a role in regulating the process of iron oxidation. In recent years, with the emergence of the concept of ferroptosis and the in-depth study of its mechanisms, ferroptosis is closely associated with various biological conditions related to kidney diseases, including kidney organ development, aging, immunity, and cancer. This article reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, and MBOAT1/2 pathways), and the latest research progress on its involvement in kidney diseases. It summarizes research on ferroptosis in kidney diseases within the frameworks of metabolism, reactive oxygen biology, and iron biology. The article introduces key regulatory factors and mechanisms of ferroptosis in kidney diseases, as well as important concepts and major open questions in ferroptosis and related natural compounds. It is hoped that in future research, further breakthroughs can be made in understanding the regulation mechanism of ferroptosis and utilizing ferroptosis to promote treatments for kidney diseases, such as acute kidney injury(AKI), chronic kidney disease (CKD), diabetic nephropathy(DN), and renal cell carcinoma. This paves the way for a new approach to research, prevent, and treat clinical kidney diseases.

The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy.

Cancer is a major disease with ever-increasing morbidity and mortality. The metabolites derived from traditional Chinese medicine (TCM) have played a significant role in combating cancers with curative efficacy and unique advantages. Ferroptosis, an iron-dependent programmed death characterized by the accumulation of lipid peroxide, stands out from the conventional forms of cell death, such as apoptosis, pyroptosis, necrosis, and autophagy. Recent evidence has demonstrated the potential of TCM metabolites targeting ferroptosis for cancer therapy. We collected and screened related articles published in or before June 2023 using PubMed, Google Scholar, and Web of Science. The searched keywords in scientific databases were ferroptosis, cancer, tumor, traditional Chinese medicine, botanical drugs, and phytomedicine. Only research related to ferroptosis, the metabolites from TCM, and cancer was considered. In this review, we introduce an overview of the current knowledge regarding the ferroptosis mechanisms and review the research advances on the metabolites of TCM inhibiting cancer by targeting ferroptosis.

Mechanistic elucidation of ferroptosis and ferritinophagy: implications for advancing our understanding of arthritis.

In recent years, the emerging phenomenon of ferroptosis has garnered significant attention as a distinctive mode of programmed cell death. Distinguished by its reliance on iron and dependence on reactive oxygen species (ROS), ferroptosis has emerged as a subject of extensive investigation. Mechanistically, this intricate process involves perturbations in iron homeostasis, dampening of system Xc-activity, morphological dynamics within mitochondria, and the onset of lipid peroxidation. Additionally, the concomitant phenomenon of ferritinophagy, the autophagic degradation of ferritin, assumes a pivotal role by facilitating the liberation of iron ions from ferritin, thereby advancing the progression of ferroptosis. This discussion thoroughly examines the detailed cell structures and basic processes behind ferroptosis and ferritinophagy. Moreover, it scrutinizes the intricate web of regulators that orchestrate these processes and examines their intricate interplay within the context of joint disorders. Against the backdrop of an annual increase in cases of osteoarthritis, rheumatoid arthritis, and gout, these narrative sheds light on the intriguing crossroads of pathophysiology by dissecting the intricate interrelationships between joint diseases, ferroptosis, and ferritinophagy. The newfound insights contribute fresh perspectives and promising therapeutic avenues, potentially revolutionizing the landscape of joint disease management.

Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications.

Ferroptosis, a recently identified type of non-apoptotic cell death, triggers the elimination of cells in the presence of lipid peroxidation and in an iron-dependent manner. Indeed, ferroptosis-stimulating factors have the ability of suppressing antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and the subsequent oxidative death of the cells. Ferroptosis is involved in the pathophysiological basis of different maladies, such as multiple cancers, among which female-oriented malignancies have attracted much attention in recent years. In this context, it has also been unveiled that non-coding RNA transcripts, including microRNAs, long non-coding RNAs, and circular RNAs have regulatory interconnections with the ferroptotic flux, which controls the pathogenic development of diseases. Furthermore, the potential of employing these RNA transcripts as therapeutic targets during the onset of female-specific neoplasms to modulate ferroptosis has become a research hotspot; however, the molecular mechanisms and functional alterations of ferroptosis still require further investigation. The current review comprehensively highlights ferroptosis and its association with non-coding RNAs with a focus on how this crosstalk affects the pathogenesis of female-oriented malignancies, from breast cancer to ovarian, cervical, and endometrial neoplasms, suggesting novel therapeutic targets to decelerate and even block the expansion and development of these tumors.

Taurine Alleviates Ferroptosis-Induced Metabolic Impairments in C2C12 Myoblasts by Stabilizing the Labile Iron Pool and Improving Redox Homeostasis.

Ferroptosis adversely affects the viability, differentiation, and metabolic integrity of C2C12 myoblasts, contributing to the decline in skeletal muscle health. The intricate mechanisms behind this process are not fully understood. In this study, we induced ferroptosis in myoblasts using targeted inducers and found a marked decrease in specific redox metabolites, particularly taurine. Taurine supplementation effectively reversed the deleterious effects of ferroptosis, significantly increased cellular glutathione levels, reduced MDA and ROS levels, and rejuvenated impaired myogenic differentiation. Furthermore, taurine downregulated HO-1 expression and decreased intracellular Fe2+ levels, thereby stabilizing the labile iron pool. Using NMR metabolomic analysis, we observed that taurine profoundly promoted glycerophospholipid metabolism, which is critical for cell membrane repair, and enhanced mitochondrial bioenergetics, thereby increasing the energy reserves essential for muscle satellite cell regeneration. These results suggest that taurine is a potent ferroptosis inhibitor that attenuates key drivers of this process, strengthens oxidative defenses, and improves redox homeostasis. This combined effect protects cells from ferroptosis-induced damage. This study highlights the potential of taurine as a valuable ferroptosis inhibitor that protects skeletal muscle from ferroptosis-induced damage and provides a basis for therapeutic strategies to rejuvenate and facilitate the regeneration of aging skeletal muscle.

FTO mediates bisphenol F-induced blood-testis barrier impairment through regulating ferroptosis via YTHDF1/TfRc and YTHDF2/SLC7A11 signal axis.

Bisphenol F (BPF) has been extensively utilized in daily life, which brings new hazards to male reproductive health. However, the specific functional mechanism is still unclear. Both cell and animal models were utilized for exploring the role of RNA methylation and ferroptosis and its underlying mechanisms in male reproductive injury induced by BPF. In animal model, BPF severely destroyed the integrity of the blood-testis barrier (BTB) and induced ferroptosis. Furthermore, BPF significantly affected the barrier function of TM4 cells and promoted ferroptosis. Importantly, ChIP assays revealed that BPF inhibited AR transcriptional regulation of FTO and FTO expression was downregulated in TM4 cells. Overexpression of FTO prevented the impairment of BTB by inhibiting ferroptosis in TM4 cells. Mechanistically, FTO could significantly down-regulate the m6A modification level of TfRc and SLC7A11 mRNA through MeRIP experiment. RIP experiments showed that YTHDF1 can bind to TfRc mRNA and promote its translation while YTHDF2 could bind to SLC7A11 mRNA and reduce its mRNA stability. Therefore, our results suggest that FTO plays a key role in BPF induced male reproductive toxicity through YTHDF1-TfRc axis and YTHDF2-SLC7A11 axis and may provide new ideas and methods for the prevention and treatment of male reproductive diseases associated with environmental pollutants.

Methane saline suppresses ferroptosis via the Nrf2/HO-1 signaling pathway to ameliorate intestinal ischemia-reperfusion injury.

OBJECTIVES: Intestinal ischemia-reperfusion (I/R) injury is a multifactorial and complex clinical pathophysiological process. Current research indicates that the pathogenesis of intestinal I/R injury involves various mechanisms, including ferroptosis. Methane saline (MS) has been demonstrated to primarily exert anti-inflammatory and antioxidant effects in I/R injury. In this study, we mainly investigated the effect of MS on ferroptosis in intestinal I/R injury and determined its potential mechanism. METHODS: In vivo and in vitro intestinal I/R injury models were established to validate the relationship between ferroptosis and intestinal I/R injury. MS treatment was applied to assess its impact on intestinal epithelial cell damage, intestinal barrier disruption, and ferroptosis. RESULTS: MS treatment led to a reduction in I/R-induced intestinal epithelial cell damage and intestinal barrier disruption. Moreover, similar to treatment with ferroptosis inhibitors, MS treatment reduced ferroptosis in I/R, as indicated by a decrease in the levels of intracellular pro-ferroptosis factors, an increase in the levels of anti-ferroptosis factors, and alleviation of mitochondrial damage. Additionally, the expression of Nrf2/HO-1 was significantly increased after MS treatment. However, the intestinal protective and ferroptosis inhibitory effects of MS were diminished after the use of M385 to inhibit Nrf2 in mice or si-Nrf2 in Caco-2 cells. DISCUSSION: We proved that intestinal I/R injury was mitigated by MS and that the underlying mechanism involved modulating the Nrf2/HO-1 signaling pathway to decrease ferroptosis. MS could be a promising treatment for intestinal I/R injury.

Cytotoxic and radical activities of metal-organic framework modified with iron oxide: Biological and physico-chemical analyses.

Metal-organic framework (MOF) modified with iron oxide, Fe3O4-MOF, is a perspective drug delivery agent, enabling magnetic control and production of active hydroxyl radicals, •OH, via the Fenton reaction. This paper studies cytotoxic and radical activities of Fe-containing nanoparticles (NPs): Fe3O4-MOF and its components - bare Fe3O4 and MOF (MIL-88B). Luminous marine bacteria Photobacteriumphosphoreum were used as a model cellular system to monitor bioeffects of the NPs. Neither the NPs of Fe3O4-MOF nor MOF showed cytotoxic effects in a wide range of concentrations (<10 mg/L); while Fe3O4 was toxic at >3·10-3 mg/L. The NPs of Fe3O4 did not affect the bacterial bioluminescence enzymatic system; their toxic effect was attributed to cellular membrane processes. The integral content of reactive oxygen species (ROS) was determined using a chemiluminescence luminol assay. Bacteria mitigated excess of ROS in water suspensions of Fe3O4-MOF and MOF, maintaining bioluminescence intensity closer to the control; this resulted in low toxicity of these NPs. We estimated the activity of •OH radicals in the NPs samples with physical and chemical methods - spin capture technology (using electron paramagnetic resonance spectroscopy) and methylene blue degradation. Physico-chemical interpretation of cellular responses is provided in terms of iron content, iron ions release and •OH radical production.

Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor.

Gut microbiota contributes to the homeostasis of immune system and is related to various diseases such as tumorigenesis. Ferroptosis, a new type of cell death, is also involved in the disease pathogenesis. Recent studies have found the correlations of gut microbiota mediated ferroptosis and immune cell death. Gut microbiota derived immunosuppressive metabolites, which can promote differentiation and function of immune cells, tend to inhibit ferroptosis through their receptors, whereas inflammatory metabolites from gut microbiota also affect the differentiation and function of immune cells and their ferroptosis. Thus, it is possible for gut microbiota to regulate immune cell ferroptosis. Indeed, gut microbiota metabolite receptor aryl hydrocarbon receptor (AhR) can affect ferroptosis of intestinal intraepithelial lymphocytes, leading to disease pathogenesis. Since immune cell ferroptosis in tumor microenvironment (TME) affects the occurrence and development of tumor, the modulation of gut microbiota in these cell ferroptosis might influence on the tumorigenesis, and also immunotherapy against tumors. Here we will summarize the recent advance of ferroptosis mediated by gut microbiota metabolites, which potentially acts as regulator(s) on immune cells in TME for therapy against tumor.

Lamivudine protects mice from gastric ulcer by activating PGK1 to suppress ferroptosis.

Gastric ulcer is a highly prevalent digestive tract disease across the world, which is recurrent and hard to cure, sometimes transforming into gastric cancer if left untreated, posing great threat to human health. To develop new medicines for gastric ulcer, we ran a series of screens with ethanol stress model in GES-1 cells, and we uncovered that lamivudine rescued cells from ethanol toxicity. Then, we confirmed this discovery using the well-established ethanol-induced gastric ulcer model in mice and our findings suggest that lamivudine can directly activate phosphoglycerate kinase 1 (PGK1, EC 2.7.2.3), which binds and stimulates superoxide dismutase 1 (SOD1, EC 1.15.1.1) to inhibit ferroptosis and ultimately improve gastric ulcer. Moreover, AAV-PGK1 exhibited comparable gastroprotective effects to lamivudine. The findings are expected to offer novel therapeutic strategies for gastric ulcer, encompassing both lamivudine and AAV-PGK1.

Ferroptosis: Latest evidence and perspectives on plant-derived natural active compounds mitigating doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a chemotherapy drug widely used in clinical settings, acting as a first-line treatment for various malignant tumors. However, its use is greatly limited by the cardiotoxicity it induces, including doxorubicin-induced cardiomyopathy (DIC). The mechanisms behind DIC are not fully understood, but its potential biological mechanisms are thought to include oxidative stress, inflammation, energy metabolism disorders, mitochondrial damage, autophagy, apoptosis, and ferroptosis. Recent studies have shown that cardiac injury induced by DOX is closely related to ferroptosis. Due to their high efficacy, availability, and low side effects, natural medicine treatments hold strong clinical potential. Currently, natural medicines have been shown to mitigate DOX-induced ferroptosis and ease DIC through various functions such as antioxidation, iron ion homeostasis correction, lipid metabolism regulation, and mitochondrial function improvement. Therefore, this review summarizes the mechanisms of ferroptosis in DIC and the regulation by natural plant products, with the expectation of providing a reference for future research and development of inhibitors targeting ferroptosis in DIC. This review explores the mechanisms of ferroptosis in doxorubicin-induced cardiomyopathy (DIC) and summarizes how natural plant products can alleviate DIC by inhibiting ferroptosis through reducing oxidative stress, correcting iron ion homeostasis, regulating lipid metabolism, and improving mitochondrial function.

CircCOL5A1 is involved in proliferation, invasion, and inhibition of ferroptosis of colorectal cancer cells via miR-1287-5p/SLC7A11.

Colorectal cancer (CRC) is the leading cause of cancer-related death globally. Circular RNA circCOL5A1 plays an oncogene function in a variety of tumors. However, the function of circCOL5A1 in CRC is still unknown. Here, we aimed to elucidate the function and mechanism of circCOL5A1 in CRC. The correlation between circCOL5A1 and CRC clinicopathological was assessed through chi-square. The relevance between circCOL5A1 and CRC patient survival time was evaluated by Kaplan-Meier analysis. The expressions of circCOL5A1 in CRC were determined via quantitative real-time PCR. The function of circCOL5A1 in CRC was analyzed with Cell Counting Kit-8, EdU assay, Transwell, detection of reactive oxygen species and Fe2+ levels, and Western blot analysis. Moreover, the mechanism of circCOL5A1 was determined by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down. Finally, the role of circCOL5A1 in vivo was elucidated through a mouse xenograft model, hematoxylin-eosin staining, and immunohistochemistry. CircCOL5A1 expression was increased in CRC, and increased circCOL5A1 levels were related to TNM stage, lymph node metastasis, distant metastasis, and tumor differentiation in CRC patients, and CRC patients with high circCOL5A1 levels had a low overall survival rate. For the circCOL5A1 function in CRC, we found that circCOL5A1 knockdown weakened CRC cell proliferation and invasion, and enhanced cell ferroptosis. For the circCOL5A1 mechanism in CRC, we further confirmed that circCOL5A1 bound to miR-1287-5p, miR-1287-5p bound to SLC7A11. SLC7A11 was negatively interrelated to miR-1287-5p and was positively interrelated to circCOL5A1 in CRC tissues. Furthermore, interfering circCOL5A1 decreased SLC7A11 expression, and this trend was abolished through miR-1287-5p cotransfection. Rescue assays further demonstrated that circCOL5A1 knockdown alleviated CRC cell malignant phenotype via miR-1287-5p/SLC7A11. Moreover, interference with circCOL5A1 reduced CRC growth in vivo. CircCOL5A1 functioned as an oncogene in CRC via miR-1287-5p/SLC7A11.

IGF2BP3 suppresses ferroptosis in lung adenocarcinoma by m6A-dependent regulation of TFAP2A to transcriptionally activate SLC7A11/GPX4.

Ferroptosis is recently discovered as an important player in the initiation, proliferation, and progression of human tumors. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported as an oncogene in multiple types of cancers, including lung adenocarcinoma (LUAD). However, little research has been designed to investigate the regulation of IGF2BP3 on ferroptosis in LUAD. qRT-PCR and western blot were used to measure the mRNA and protein expression of IGF2BP3 and transcription factor AP-2 alpha (TFAP2A). CCK-8 assay was performed to determine cell viability. DCFH-DA and C11-BODIPY staining were used to detect the levels of intracellular reactive oxygen species (ROS) and lipid ROS. The corresponding assay kits were used to analyze the levels of malondialdehyde (MDA) and glutathione (GSH). SRAMP website and m6A RNA immunoprecipitation (Me-RIP) were used to predict and confirm the m6A modification of TFAP2A. RIP experiments were conducted to confirm the binding of IGF2BP3 and TFAP2A. RNA stability assay was performed using actinomycin D. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter experiments were performed to confirm the interaction between TFAP2A and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4). Mice xenotransplant model was also constructed to explore the effect of IGF2BP3 on LUAD tumor growth and ferroptosis. IGF2BP3 and TFAP2A were both highly expressed in LUAD. IGF2BP3 or TFAP2A knockdown induced ferroptosis by aggravating erastin-induced cell viability suppression, increasing the production of intracellular ROS, lipid ROS, and MDA, and decreasing GSH synthesis, GSH/GSSG ratio, and cystine uptake. Mechanistically, IGF2BP3 stabilized TFAP2A expression via m6A modification. Moreover, sh-IGF2BP3-mediated ferroptosis was significantly abated by TFAP2A overexpression. Furthermore, TFAP2A binds to the promoters of SLC7A11 and GPX4 to promote their transcription. Also, IGF2BP3 depletion suppressed LUAD tumor growth by inducing ferroptosis in mice. IGF2BP3 suppresses ferroptosis in LUAD by m6A-dependent regulation of TFAP2A to promote the transcription of SLC7A11 and GPX4. Our findings suggest that targeting IGF2BP3/TFAP2A/SLC7A11/GPX4 axis might be a potential therapeutic choice to increase ferroptosis sensitivity in LUAD.

Quercetin Attenuates Acute Kidney Injury Caused by Cisplatin by Inhibiting Ferroptosis and Cuproptosis.

Ferroptosis, an iron- and ROS-dependent form of regulated cell death. Cuproptosis is a novel form of cellular demise mode. Quercetin, a natural flavonoid, has demonstrated a range of pharmacological activities, including anti-cancer, anti-inflammatory, and antioxidant properties. In this research, we investigated the quercetin effect on cisplatin-induced acute kidney and its mechanism associated ferroptosis and cuproptosis. The HK-2 cells were used in this research. Cell viability was evaluated using the CCK-8 assay. Acute kidney injury (AKI) models were established to perform in vivo experiments. Renal tissue homogenate was used to determine ROS, LPO, MDA, PA, etc., to assess ferroptosis and cuproptosis. To perform bioinformatic analysis, microarray data from the GEO database was utilized. Real-time PCR analysis and ELISA was explored the mechanism of ferroptosis and cuproptosis. We found that ferroptosis and cuproptosis in AKI were abnormally activated caused by cisplatin, and that quercetin attenuated AKI by inhibiting ferroptosis and cuproptosis. QCT suppressed ferroptosis by reducing malondialdehyde (MDA) and ROS levels and increasing glutathione (GSH) levels and alleviated cuproptosis by reducing copper ion, pyruvate (PA) and HSP70 levels. Moreover, bioinformatic analysis revealed that the ferroptosis-related gene SLC7A11 and the cuproptosis-related genes ATP7B and GLS were the differential expression genes. And QCT significantly increased the expression or activity of SLC7A11, GPX4, ATP7B, and GLS in Cis-AKI mice. Our findings highlight the clinical importance of quercetin, which guards against cisplatin-induced acute kidney injury by suppressing ferroptosis and cuproptosis.

Thiostrepton induces oxidative stress, mitochondrial dysfunction and ferroptosis in HaCaT cells.

TST has been mainly studied for its anti-tumor proliferation and antimicrobial effects, but not widely used in dermatological diseases. The mechanism of cellular damage by TST in response to H2O2-mediated oxidative stress was investigated in human skin immortalized keratinocytes (HaCaT) as an in vitro model. The findings reveal that TST treatment leads to increased oxidative stress in the cells by reducing levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). This effect is further supported by an upsurge in the expression of malondialdehyde (MDA, a pivotal marker of lipid peroxidation). Additionally, dysregulation of FoxM1 at both gene and protein levels corroborates its involvement TST associated effects. Analysis of ferroptosis-related genes confirms dysregulation following TST treatment in HaCaT cells. Furthermore, TST treatment exhibits effects on mitochondrial morphology and function, affirming its induction of apoptosis in the cells through heightened oxidative stress due to mitochondrial damage and dysregulation of mitochondrial membrane potential.

Synergy between nanoplastics and benzo[a]pyrene promotes senescence by aggravating ferroptosis and impairing mitochondria integrity in Caenorhabditis elegans.

Micro-nano plastics have been reported as important carriers of polycyclic aromatic hydrocarbons (PAHs) for long-distance migration in the environment. However, the combined toxicity from long-term chronic exposure beyond the vehicle-release mechanism remains elusive. In this study, we investigated the synergistic action of Benzo[a]pyrene (BaP) and Polystyrene nanoparticles (PS) in Caenorhabditis elegans (C. elegans) as a combined exposure model with environmental concentrations. We found that the combined exposure to BaP and PS, as opposed to single exposures at low concentrations, significantly shortened the lifespan of C. elegans, leading to the occurrence of multiple senescence phenotypes. Multi-omics data indicated that the combined exposure to BaP and PS is associated with the disruption of glutathione homeostasis. Consequently, the accumulated reactive oxygen species (ROS) cannot be effectively cleared, which is highly correlated with mitochondrial dysfunction. Moreover, the increase in ROS promoted lipid peroxidation in C. elegans and downregulated Ferritin-1 (Ftn-1), resulting in ferroptosis and ultimately accelerating the aging process of C. elegans. Collectively, our study provides a new perspective to explain the long-term compound toxicity caused by BaP and PS at real-world exposure concentrations.

Mechanisms of exacerbation of Th2-mediated eosinophilic allergic asthma induced by plastic pollution derivatives (PPD): A molecular toxicological study involving lung cell ferroptosis and metabolomics.

Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.