New Type Of Cell Death Research Articles

Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases.

Ferroptosis is a new type of cell death characterized by iron dependence and the excessive accumulation of lipid reactive oxygen species (lipid ROS) that has gradually become better characterized. There is sufficient evidence indicating that ferroptosis is associated with a variety of human life activities and diseases, such as tumor suppression, ischemic organ injury, and degenerative disorders. Notably, ferroptosis is also involved in the initiation and development of fibrosis in various organs, including liver fibrosis, pulmonary fibrosis, renal fibrosis, and cardiac fibrosis, which is usually irreversible and refractory. Although a large number of patients with fibrosis urgently need to be treated, the current treatment options are still limited and unsatisfactory. Organ fibrosis involves a series of complex and orderly processes, such as parenchymal cell damage, recruitment of inflammatory cells and activation of fibroblasts, which ultimately leads to the accumulation of extracellular matrix (ECM) and the formation of fibrosis. An increasing number of studies have confirmed the close association between these pathological processes and ferroptosis. This review summarizes the role and function of ferroptosis in fibrosis and proposes several potential therapeutic strategies and pathways based on ferroptosis.

FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury.

Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repair. In this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction. Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21. FGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair.

Iron Overload Induces Hepatic Ferroptosis and Insulin Resistance by Inhibiting the Jak2/stat3/slc7a11 Signaling Pathway.

Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload.

Magnesium hexacyanoferrate nanocatalysts alleviates fibromyalgia syndrome by reversing cellular ferroptosis

Fibromyalgia (FM), the most common causes of chronic musculoskeletal pain, is a complex syndrome with an indefinite etiology. Ferroptosis is a new type of cell death characterized by iron-dependent lipid peroxidation, affecting many chronic pain diseases. Here, we confirmed the role of ferroptosis in FM using a mouse model of reserpine induction. Then, we developed polyvinylpyrrolidone-assembled magnesium hexacyanoferrate nanocatalysts (MgHCF NCs) as a new type of ferroptosis inhibitor, for its efficacy in ferrous ions capture and antioxidation. Excellent in vivo FM-alleviation effect from MgHCF NCs was demonstrated. The FM-protective and antiferroptotic efficacy of MgHCF NCs at the transcriptional level were explored by whole-transcriptome analysis. Meanwhile, the remarkable antiferroptotic effect of MgHCF NCs was further validated in vitro ferroptosis-inducer experiments, which was firmly associated with the efficacy of MgHCF NCs on reducing oxidative stress, mitochondrial protection and correcting disordered polyunsaturated fatty acids (PUFAs) metabolism. The excellent antiferroptotic effect and biocompatibility render MgHCF NCs to be highly promising and clinically transformable agents for FM treatment.

USP13 regulates ferroptosis in chicken follicle granulosa cells by deubiquitinating ATG7

The development and maturation of follicles are intricately linked to egg production and reproductive performance of chickens. Granulosa cells death directly affects the development and maturation of follicles, thereby impacting the reproductive performance of hens. Ferroptosis is a new type of cell death, it is unknown how it affects the growth and development of chicken follicles. In this study, RNA-seq analysis revealed significant differences in the expression of ferroptosis-related genes between normal follicles and atretic follicles, suggesting a potential role for ferroptosis in follicle growth and development. In addition, we found that ubiquitin-specific protease 13 (USP13) was significantly upregulated in atrophic follicles. Overexpression of USP13 results in depletion of glutathione (GSH), peroxidation of lipids, accumulation of iron, and activation of ferroptosis in chicken granulosa cells. In contrast, USP13 knockdown significantly inhibited ferroptosis events. Mechanistically, USP13 prevents the degradation of autophagy related 7 (ATG7) by deubiquitinating it, thereby enhancing the stability of ATG7 protein and ultimately promoting ferroptosis. In conclusion, this study elucidates the crucial role of the USP13-ATG7 axis in regulating ferroptosis in chicken follicle granulosa cells, thereby presenting a novel avenue for molecular breeding research in chickens.

M6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.

Blocking Runx2 Inhibits the Caspase-1 Dependent Pyroptosis in Lipopolysaccharide-Treated Chondrocyte

Pyroptosis is a new type of cell death in the development of osteoarthritis (OA), but the underlying mechanism is not fully understood. This study aimed to investigate the role of Runx2 in the pyroptosis of chondrocyte (CH) and explore its effect on Caspase-1 expression. Human knee tissues from the fracture patients without OA history were collected. Human CHs isolated from the tissue were treated by lipopolysaccharide (LPS) to establish the model of OA. siRNA and CADD522 were used to block the function of Runx2. The cell viability was tested by MTT. The expression levels of Runx2, Caspase1/4/5/11, GSDMD, collagen-II, aggrecan, IL-1β, IL-8, and MMP3/9 were detected by RT-PCR, immunofluorescence, or western blot. Besides, the transcriptional association between Runx2 and Caspase-1 was confirmed by DNA immunoprecipitation and luciferase reporter assay. Runx2 and Caspase-1 expression were increased in LPS-treated CHs. Runx2 bound to the promoter of Caspase-1 and activated its expression. Moreover, silencing Runx2 or disrupting the DNA-binding ability of Runx2 attenuated the LPS-induced pyroptotic phenotype, containing Caspase-1 activation, collagen-II and aggrecan degradation, viability suppression, IL-1β and IL-8 upregulation. Blocking the expression or function of Runx2 alleviated the LPS-caused pyroptosis in CHs in the Caspase-1 manner, indicating a novel understanding of the pathology of OA.

Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.

Cadmium Induces Kidney Iron Deficiency and Chronic Kidney Injury by Interfering with the Iron Metabolism in Rats.

Cadmium (Cd) is a common environmental pollutant and occupational toxicant that seriously affects various mammalian organs, especially the kidney. Iron ion is an essential trace element in the body, and the disorder of iron metabolism is involved in the development of multiple pathological processes. An iron overload can induce a new type of cell death, defined as ferroptosis. However, whether iron metabolism is abnormal in Cd-induced nephrotoxicity and the role of ferroptosis in Cd-induced nephrotoxicity need to be further elucidated. Sprague Dawley male rats were randomly assigned into three groups: a control group, a 50 mg/L CdCl2-treated group, and a 75 mg/L CdCl2-treated group by drinking water for 1 month and 6 months, respectively. The results showed that Cd could induce renal histopathological abnormalities and dysfunction, disrupt the mitochondria's ultrastructure, and increase the ROS and MDA content. Next, Cd exposure caused GSH/GPX4 axis blockade, increased FTH1 and COX2 expression, decreased ACSL4 expression, and significantly decreased the iron content in proximal tubular cells or kidney tissues. Further study showed that the expression of iron absorption-related genes SLC11A2, CUBN, LRP2, SLC39A14, and SLC39A8 decreased in proximal tubular cells or kidneys after Cd exposure, while TFRC and iron export-related gene SLC40A1 did not change significantly. Moreover, Cd exposure increased SLC11A2 gene expression and decreased SLC40A1 gene expression in the duodenum. Finally, NAC or Fer-1 partially alleviated Cd-induced proximal tubular cell damage, while DFO and Erastin further aggravated Cd-induced cell damage. In conclusion, our results indicated that Cd could cause iron deficiency and chronic kidney injury by interfering with the iron metabolism rather than typical ferroptosis. Our findings suggest that an abnormal iron metabolism may contribute to Cd-induced nephrotoxicity, providing a novel approach to preventing kidney disease in clinical practice.

Inhibition of ferroptosis underlies EGCG mediated protection against Parkinson’s disease in a Drosophila model

Ferroptosis, a new type of cell death accompanied by iron accumulation and lipid peroxidation, is implicated in the pathology of Parkinson's disease (PD), which is a prevalent neurodegenerative disorder that primarily occurred in the elderly population. Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea with known neuroprotective effects in PD patients. But whether EGCG-mediated neuroprotection against PD involves regulation of ferroptosis has not been elucidated. In this study, we established a PD model using PINK1 mutant Drosophila. Iron accumulation, lipid peroxidation and decreased activity of GPX, were detected in the brains of PD flies. Additionally, phenotypes of PD, including behavioral defects and dopaminergic neurons loss, were ameliorated by ferroptosis inhibitor ferrostatin-1 (Fer-1). Notably, the increased iron level, lipid peroxidation and decreased GPX activity in the brains of PD flies were relieved by EGCG. We found that EGCG exerted neuroprotection mainly by restoring iron homeostasis in the PD flies. EGCG inhibited iron influx by suppressing Malvolio (Mvl) expression and simultaneously promoted the upregulation of ferritin, the intracellular iron storage protein, leading to a reduction in free iron ions. Additionally, EGCG downregulated the expression of Duox and Nox, two NADPH oxidases that produce reactive oxygen species (ROS) and increased SOD enzyme activity. Finally, modulation of intracellular iron levels or regulation of oxidative stress by genetic means exerted great influence on PD phenotypes. As such, the results demonstrated that ferroptosis has a role in the established PD model. Altogether, EGCG has therapeutic potentials for treating PD by targeting the ferroptosis pathway, providing new strategies for the prevention and treatment of PD and other neurodegenerative diseases.

Global trends in PANoptosis research: bibliometrics and knowledge graph analysis.

PANoptosis has recently been discovered as a new type of cell death. PANoptosis mainly refers to the significant interaction among the three programmed cell death pathways of apoptosis, necroptosis, and pyroptosis. Despite this, only a few studies have examined the systematic literature in this area. By analyzing the bibliometric data for PANoptosis, we can visualize the current hotspots and predicted trends in research. This study analyzed bibliometric indicators using the Histcite Pro 2.0 tool, which searches the Web of Science for PANoptosis literature published between 2016 and 2022. A bibliometric analysis was performed using Histcite Pro 2.0, while research trends and hotspots were visualized using VOSviewer, CiteSpace and BioBERT. The output of related literature was low in the four years from the first presentation of PANoptosis in 2016 to 2020. The volume of relevant literature grew exponentially between 2020 and 2022. The United States and China play a leading role in this field. Although China started late, its research in this field is developing rapidly. As research progressed, more focus was placed on the relationship between PANoptosis and pyroptosis, as well as apoptosis and necrosis. Now is a rapid development stage of PANoptosis research. Most of the research focuses on the cellular level, and the focus is more on the treatment of tumor-related diseases. The current focus of this area is PANoptosis mechanisms in cancer and inflammation. It can be seen from the burst analysis of keywords that caspase1 and host defense have consistently been research hotspots in the field of PANoptosis, while the frequency of NLRC4, causes of autoinflammation, recognition, NLRP3, and GasderminD has gradually increased, all of which have become research hotspots in recent years. Finally, we used the BioBERT biomedical language model to mine the most documented genes and diseases in the PANoptosis field articles, pointing out the direction for subsequent research steps. According to a bibliometric analysis, researchers have shown an increased interest in PANoptosis over the past few years. Researchers initially focused on the molecular mechanism of PANoptosis and pyroptosis, apoptosis, and necroptosis. The role of PANoptosis in diseases and conditions such as inflammation and tumors is one of the current research hotspots in this area. The focus is more on treating inflammation-related diseases, which will become the key development direction of future research.

Azurocidin 1 inhibits the aberrant proliferation of triple‑negative breast cancer through the regulation of pyroptosis.

Azurocidin 1 (AZU1) is a heparin‑binding protein which has been reported to be aberrantly expressed in various tumors, but its definite role in breast cancer (BC) has not been clarified. The aim of the present study was to explore the associations between AZU1 and BC. In the present study, bioinformatics and western blot analyses were applied to detect the expression level of AZU1 in BC tissues. The effect of AZU1 on cell proliferation and apoptosis was analyzed using Cell Counting Kit‑8 assay, colony formation assay and flow cytometry. Based on bioinformatics analysis, AZU1 exhibited low expression in tissues and was negatively associated with the survival rate of patients with triple‑negative BC (TNBC). Exogenous AZU1 stimuli significantly inhibited the proliferation and colony formation of TNBC cell lines. Furthermore, the data of flow cytometry revealed that exogenous AZU1 stimuli enhanced apoptosis in MDA‑231 and BT‑549 cells. As pyroptosis is a new type of cell death, the effects AZU1 played on the expression of gasdermin D (GSDMD), a specific biomarker of pyroptosis, were also investigated. The findings of the present study revealed that GSDMD, as well as its upstream regulators [NF‑κB, NLR family pyrin domain containing3 (NLRP3) and caspase‑1], were significantly increased in TNBC cell lines when treated with exogenous AZU1, indicating that AZU1 contributed to the inhibition of pyroptosis of TNBC cell lines through the NF‑κB/NLRP3/caspase‑1 axis. Collectively, it was revealed for the first time, that AZU1 exposure promoted pyroptosis through the modulation of the pNF‑κB/NLRP3/caspase‑1/GSDMD axis in TNBC invitro. The findings of the present study unveiled a novel mechanism of AZU1‑induced pyroptosis in TNBC, which may aid in developing new strategies for therapeutic interventions in TNBC. breast cancer is the most commone form of cancer in women and is second only to lung cancer in terms of cancer‑related mortality.

Metformin alleviates glucolipotoxicity-induced pancreatic β cell ferroptosis through regulation of the GPX4/ACSL4 axis

Ferroptosis, a new type of cell death, is associated with pancreatic β cell damage. However, the role of glucolipotoxicity in inducing β cell ferroptosis remains unclear. Metformin (Met), exenatide (Exe), and saxagliptin (Sax) are frequently used anti-hyperglycaemic drugs. However, their protective effects on β cells through ferroptosis modulation are not well-established. In this study, we observed significant ferroptosis in NIT-1 cells and primary mouse islets after exposure to high glucose and palmitate (HG/PA). Compared to Exe and Sax, Met significantly alleviated glucolipotoxicity-induced pancreatic β cell ferroptosis. Blocking the activity of glutathione peroxidase 4 (GPX4) with Ras-selective lethal 3 or inhibiting its expression by small interfering RNA transfection significantly attenuated the anti-ferroptosis effects of Met. Mechanistically, Met alleviates HG/PA-induced β cell ferroptosis by regulating the GPX4/ACSL4 axis. Collectively, our findings highlight the significance of ferroptosis in pancreatic β cell glucolipotoxicity-induced injury and provide novel insights into the protective effects of Met on islet β cells.

Construction of a risk model and prediction of prognosis and immunotherapy based on cuproptosis-related LncRNAs in the urinary system pan-cancer

BackgroundUrinary pan-cancer system is a general term for tumors of the urinary system including renal cell carcinoma (RCC), prostate cancer (PRAD), and bladder cancer (BLCA). Their location, physiological functions, and metabolism are closely related, making the occurrence and outcome of these tumors highly similar. Cuproptosis is a new type of cell death that is different from apoptosis and plays an essential role in tumors. Therefore, it is necessary to study the molecular mechanism of cuproptosis-related lncRNAs to urinary system pan-cancer for the prognosis, clinical diagnosis, and treatment of urinary tumors.MethodIn our study, we identified 35 co-expression cuproptosis-related lncRNAs (CRLs) from the urinary pan-cancer system. 28 CRLs were identified as prognostic-related CRLs by univariate Cox regression analysis. Then 12 CRLs were obtained using lasso regression and multivariate cox analysis to construct a prognostic model. We divided patients into high- and low-risk groups based on the median risk scores. Next, Kaplan–Meier analysis, principal component analysis (PCA), functional rich annotations, and nomogram were used to compare the differences between the high- and low-risk groups. Finally, the prediction of tumor immune dysfunction and rejection, gene mutation, and drug sensitivity were discussed.ConclusionFinally, the candidate molecules of the urinary system pan-cancer were identified. This CRLs risk model may be promising for clinical prediction of prognosis and immunotherapy response in urinary system pan-cancer patients.

Frataxin inhibits the sensitivity of the myocardium to ferroptosis by regulating iron homeostasis

RationaleMyocardial ischemia/reperfusion (I/R) injury is characterized by cell death via various cellular mechanisms upon reperfusion. As a new type of cell death, ferroptosis provides new opportunities to reduce myocardial cell death. Ferroptosis is known to be more active during reperfusion than ischemia. However, the mechanisms regulating ferroptosis during ischemia and reperfusion remain largely unknown. MethodsThe contribution of ferroptosis in ischemic and reperfused myocardium were detected by administered of Fer-1, a ferroptosis inhibitor to C57BL/6 mice, followed by left anterior descending (LAD) ligation surgery. Ferroptosis was evaluated by measurement of cell viability, ptgs2 mRNA level, iron production, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. H9C2 cells were exposed to hypoxia/reoxygenation to mimic in vivo I/R. We used LC-MS/MS to identify potential E3 ligases that interacted with frataxin in heart tissue. Cardiac-specific overexpression of frataxin in whole heart was achieved by intracardiac injection of frataxin, carried by adeno-associated virus serotype 9 (AAV9) containing cardiac troponin T (cTnT) promoter. ResultsWe showed that regulators of iron metabolism, especially iron regulatory protein activity, were increased in the ischemic myocardium or hypoxia cardiomyocytes. In addition, we found that frataxin, which is involved in iron metabolism, is differentially expressed in the ischemic and reperfused myocardium and involved in the regulation of cardiomyocytes ferroptosis. Furthermore, we identified an E3 ligase, NHL repeat-containing 1 (NHLRC1), that mediates frataxin ubiquitination degradation. Cardiac-specific overexpression of frataxin ameliorated myocardial I/R injury through ferroptosis inhibition. ConclusionsThrough a multi-level study from molecule to animal model, these findings uncover the key role of frataxin in inhibiting cardiomyocyte ferroptosis and provide new strategies and perspectives for the treatment of myocardial I/R injury.

CHARACTERISTICS OF FERROPTOSE INDUCTORS (REVIEW)

Ferroptosis is an iron-dependent non-apoptotic form of regulated cell death. In 2012, the anti-cancer activity of erastin was shown, based on the induc-tion of a new type of cell death, which is prevented by iron chelators and lipophilic antioxidants. The term "ferroptosis" has been proposed to character-ize this iron-dependent, non-apoptotic form of cell death. The purpose of this work is to evaluate and classify the range of compounds capable of in-ducing ferroptosis in various cell types. Glutathione (GSH), a common intracellular antioxidant, is required for the activity of various antioxidant enzymes (eg, GPX4). Erastine inhibits the uptake of cystine by the cystine/glutamate antiporter, creating a defect in the cell's antioxidant defenses and leading to iron-dependent oxidative death. GPX4 is a selenium-containing enzyme that catalyzes the reduction of organic hydroperoxides and lipid peroxides by reduced glutathione. The study re-vealed two promising compounds, named RSL3 and RSL5 by the authors. Tert-butyl hydroperoxide (t-BuOOH) is such a lipid peroxide analog and is widely regarded as a lipid peroxidation stimulant. Exposure to t-BuOOH resulted in a ferrostatin-1 and liprostatin-1 sensitive increase in lipid peroxidation. An excess of non-heme iron (Fe2+ and Fe3+) causes ferroptosis. Live/dead cell viability analysis showed that Fe(III)-citrate, erastin and RSL3 induce cell death. Co-treatment with ferrostatin-1, an inhibitor of ferroptosis, inhibited cell death. Other materials can cause ferroptosis by inducing lipid peroxidation. Mitochondrial DNA damaging drugs such as zalcitabine induce autophagy-dependent ferroptosis in human pancreatic cancer cells. The implementation of the model of cell death in the form of ferroptosis is highly dependent on the state of cellular metabolism and degradation systems, such as autophagy, which form a complex network for the formation of oxidative stress. Pharmacological induction of ferroptosis is a promising direction in cancer chemotherapy.

Autophagy-mediated ferroptosis involved in nickel-induced nephrotoxicity in the mice

Nickel, as a widely polluted metal, has been shown nephrotoxicity. Ferroptosis is a new type of cell death driven by iron-dependent lipid peroxidation. Our study found that nickel chloride (NiCl2) induced ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl2 treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl2. Moreover, NiCl2 increased COX-2 protein levels, decreased SLC7A11 and GPX4 protein levels, and elevated Ptgs2 mRNA levels. Next, the mechanism of Ni-induced ferroptosis was investigated. The results showed that NiCl2 induced autophagy in TCMK-1 cells, which promoted ferroptosis induced by NiCl2. Furthermore, the data of autophagy activation or inhibition experiment showed that autophagy facilitated ferroptosis through the degradation of the iron regulation protein NCOA4 and FTH1. Otherwise, iron chelator DFOM treatment inhibited ferroptosis induced by NiCl2. Finally, ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl2. To sum up, our above results showed that ferroptosis is involved in NiCl2-induced nephrotoxicity, and NiCl2 induces autophagy-dependent ferritin degradation, releases iron ions, leads to iron overload, and induces ferroptosis. This study supplies a new theoretical foundation for the study of nickel and renal toxicity.

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis.

Approximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models. We used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion. mPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells. BMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

Cuproptosis-a potential target for the treatment of osteoporosis.

Osteoporosis is an age-related disease of bone metabolism marked by reduced bone mineral density and impaired bone strength. The disease causes the bones to weaken and break more easily. Osteoclasts participate in bone resorption more than osteoblasts participate in bone formation, disrupting bone homeostasis and leading to osteoporosis. Currently, drug therapy for osteoporosis includes calcium supplements, vitamin D, parathyroid hormone, estrogen, calcitonin, bisphosphates, and other medications. These medications are effective in treating osteoporosis but have side effects. Copper is a necessary trace element in the human body, and studies have shown that it links to the development of osteoporosis. Cuproptosis is a recently proposed new type of cell death. Copper-induced cell death regulates by lipoylated components mediated via mitochondrial ferredoxin 1; that is, copper binds directly to the lipoylated components of the tricarboxylic acid cycle, resulting in lipoylated protein accumulation and subsequent loss of iron-sulfur cluster proteins, leading to proteotoxic stress and eventually cell death. Therapeutic options for tumor disorders include targeting the intracellular toxicity of copper and cuproptosis. The hypoxic environment in bone and the metabolic pathway of glycolysis to provide energy in cells can inhibit cuproptosis, which may promote the survival and proliferation of various cells, including osteoblasts, osteoclasts, effector T cells, and macrophages, thereby mediating the osteoporosis process. As a result, our group tried to explain the relationship between the role of cuproptosis and its essential regulatory genes, as well as the pathological mechanism of osteoporosis and its effects on various cells. This study intends to investigate a new treatment approach for the clinical treatment of osteoporosis that is beneficial to the treatment of osteoporosis.