Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well ...Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well established as a primary mechanism underlying follicular atresia,the potential involvement of ferroptosis,which is an irondependent form of regulated cell death,remains largely unexplored in chickens.Results Using a tamoxifen(TMX)-induced avian model of follicular atresia,we demonstrated that ferroptosis plays a critical role in follicular degeneration.Inhibition of ferroptosis through pharmacological agents significantly restored follicular function,underscoring its potential as a therapeutic target.Notably,we observed a significant upregulation of ubiquitin-specific peptidase 9,X-linked(USP9X)in GCs during atresia.Through comprehensive in vitro and in vivo investigations,we confirmed that USP9X facilitates follicular atresia by promoting ferroptosis in GCs.Mechanistically,USP9X induces ferroptosis by stabilizing Beclin1 through deubiquitination,thereby activating autophagy-dependent ferroptosis.This pathway was effectively suppressed by autophagy inhibitors,emphasizing the essential role of autophagy in USP9X-mediated ferroptosis.Conclusions Our findings provide the evidence that the USP9X-Beclin1 axis regulates autophagy-dependent ferroptosis during avian follicular atresia.These insights reveal novel molecular targets and potential genetic markers for improving reproductive efficiency in chicken breeding programs.展开更多
The issue of microplastic(MPs)pollution has received increased attention in recent years.Studies have indicated that inhalation of microplastics may result in the cardiovascular harm.However,the specific mechanism rem...The issue of microplastic(MPs)pollution has received increased attention in recent years.Studies have indicated that inhalation of microplastics may result in the cardiovascular harm.However,the specific mechanism remains to be elucidated.In this study,5μm polystyrene microplastics(PS-MPs)were employed to construct in vivo and in vitro exposure models to investigate the potential mechanisms of microplastic-induced cardiac fibrosis.In vivo model of respiratory exposure to MPs,echocardiography observed a decrease in systolic-diastolic function of the mouse heart,and myocardial tissue showed significant mitochondrial morphological abnormalities and myocardial fibrosis.In vitro models also revealed upregulation of fibrosis indicators in human cardiomyocytes AC16 cells.Transcriptome and RT-qPCR assay exposed that ferroptosis-related pathways were significantly gath-ered in the MPs group,with decreased expression of ferroptosis related genes SLC7A11 and GPX4.Liproxstatin-1(Lip-1),a ferroptosis inhibitor,significantly ameliorated MPs-induced cardiomyocyte fibrosis and ferroptosis.We further demonstrated that inhibition of hypoxia-inducible factor𝛼(HIF-𝛼)and oxidative stress ameliorated PS-MPs-induced cardiomyocyte ferroptosis,and thus upregulation of the HIF pathway and oxidative stress may be the upstream mechanism of MPs-induced ferroptosis in myocardial fibrosis.Above all,our study demonstrated that MPs exposure resulted in cardiac fibrosis via the HIF-ROS-SLC7A11/GPX4 signaling pathway.展开更多
Metal ion homeostasis plays a pivotal role in maintaining cellular functions,and its disruption can initiate regulated cell death pathways.Despite its therapeutic potential,metal ion therapy for breast cancer has been...Metal ion homeostasis plays a pivotal role in maintaining cellular functions,and its disruption can initiate regulated cell death pathways.Despite its therapeutic potential,metal ion therapy for breast cancer has been hampered by inefficient ion delivery and the intrinsic resistance mechanisms of cancer cells.In this work,a cuproptosis amplifier of copper-telaglenastat coordinate(denoted as Cu-CB) is developed to trigger cell ferroptosis for synergistic breast cancer treatment.Telaglenastat(CB-839),a glutaminase inhibitor,is identified as an effective copper ionophore that facilitates the formation of Cu-CB.Specially,Cu-CB can promote the aggregation of lipoylated proteins to initiate cuproptosis,while also inhibiting glutathione(GSH) synthesis and downregulating glutathione peroxidase 4(GPX4) to trigger ferroptosis.The interplay between these cuproptosis and apoptosis pathways,mediated by Cu-CB,significantly amplifies reactive oxygen species(ROS) production and lipid peroxidation,culminating in the synergistic suppression of breast cancer.Both in vitro and in vivo studies validate the superior antitumor effects of Cu-CB through the induction of cuproptosis and ferroptosis,which may provide a new insight for metal ion delivery systems and metal ion-based tumor therapies.展开更多
Vine tea is documented in ancient Chinese books as having the function of promoting blood circulation.However,its effects and mechanisms remain unclear.The aim of this study was to comprehensively investigate the prot...Vine tea is documented in ancient Chinese books as having the function of promoting blood circulation.However,its effects and mechanisms remain unclear.The aim of this study was to comprehensively investigate the protective potential and mechanisms of vine tea in high-fat diet rat through a combination of in vivo and in vitro experiments.The efficacy of vine tea was evaluated using a high-fat diet rat model and an oxidized low-density lipoprotein-treated cell model,with physiological and biochemical indicators measured in rat serum and cell supernatants.Transcriptomics was utilized to investigate alterations mRNA expression following the administration of dihydromyricetin in cell model.Metabolomics and 16S rRNA sequencing was employed to examine changes in metabolites in the serum and changes in gut microbiota of high-fat diet rats after administering vine tea extract.Vine tea extract and dihydromyricetin can reduce elevated levels of lipids,including total cholesterol and triglycerides,following modeling.Transcriptomic data indicate that dihydromyricetin exerts its effects by regulating ferroptosis signaling pathways.Metabolomic analysis demonstrates that the administration of vine tea extract influences the vitamin K cycle and glutathione,thereby alleviating the progression of ferroptosis.Additionally,16S rRNA sequencing reveals that vine tea extract increases Lactobacillaceae in the gut microbiota,which subsequently affects the levels of lysophosphatidylcholine,a major phospholipid component of oxidized low-density lipoprotein in serum.Our results indicate that vine tea can regulate ferroptosis signaling pathways and increase Lactobacillaceae in the gut microbiota,thereby exhibiting cardiovascular protective effects in high-fat diet rats.展开更多
Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidas...Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidase 4 axis,iron and lipid metabolism chaos,the NAD(P)Hferroptosis suppressor protein 1—ubiquinone axis,and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis.Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins,differing fundamentally from ferroptosis.Both ferroptosis and cuproptosis exhibit dual roles(promote or inhibit)in cancers.And the sensitivity of different cancer types to ferroptosis varies,which may depend on special metabolic signatures(e.g.,E-cadherin loss causes epithelial–mesenchymal transition,making tumors gain resistance to ferroptosis)and expression of antioxidant defense regulators(e.g.,high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive).At present,traditional Chinese herbal medicine,combination therapy,and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis.In this review,we have summarized the core mechanisms of ferroptosis,ferroptosis differences from cuproptosis,its impact on cancers,and its translational implications in cancer therapy,helping readers quickly get the new information and horizons on them.展开更多
Colorectal cancer(CRC), one of the leading causes of cancer-related mortality globally, urgently requires complementary and alternative therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by ...Colorectal cancer(CRC), one of the leading causes of cancer-related mortality globally, urgently requires complementary and alternative therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising anticancer strategy. Dendrobium officinale(D. officinale), a renowned traditional Chinese medicinal herb, is widely used in several Asian countries for its nutritional and therapeutic benefits.Although D. officinale has demonstrated anti-tumor effects, the molecular mechanisms underlying its action against CRC remain incompletely characterized. This study aimed to elucidate the role of D. officinale in suppressing CRC through the induction of ferroptosis and its regulatory effects on glutathione peroxidase 4(GPX4), a key suppressor of ferroptosis. In vitro assays were conducted using HCT116 and SW480 CRC cell lines, and in vivo efficacy was evaluated in BALB/c nude mice bearing CRC xenografts. D. officinale significantly reduced CRC cell viability and proliferation in vitro and suppressed tumor growth in vivo. Induction of ferroptosis was evidenced by elevated levels of Fe^(2+), malondialdehyde(MDA), and lipid peroxidation, along with a depleted glutathione/oxidized glutathione disulfide(GSH/GSSG) ratio. Notably, these effects were reversed by ferroptosis inhibitors, including ferrostatin-1(Fer-1) and deferoxamine. Consistently, D. officinale markedly downregulated GPX4 expression. Overexpression of GPX4 rescued D. officinale-induced ferroptosis, whereas GPX4 silencing exacerbated this effect. D. officinale suppresses CRC by triggering GPX4-dependent ferroptosis,providing a novel, naturally derived therapeutic approach. These findings bridge traditional medicine and modern oncology, establishing a foundation for developing targeted CRC treatments.展开更多
Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance...Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.展开更多
Ferroptosis has exhibited great potential in therapies and intracellular reducing agents of sulfur species(RSSs) in the thiol-dependent redox systems are crucial in ferroptosis.This makes the simultaneous detection of...Ferroptosis has exhibited great potential in therapies and intracellular reducing agents of sulfur species(RSSs) in the thiol-dependent redox systems are crucial in ferroptosis.This makes the simultaneous detection of multiple RSSs significant for evaluating ferroptosis therapy.However,the traditional techniques,including fluorescent(FL) imaging and electrospray ionization-based mass spectrometry(MS) detection,cannot achieve the discrimination of different RSSs.Herein,simultaneous MS detection of multiple RSSs,including cysteine(Cys),homocysteine(Hcy),glutathione(GSH) and hydrogen sulfide(H_(2)S),was obtained upon enhancing ionization efficiency by a fluorescent probe(NBD-O-1).Based on the interaction between NBD-O-1 and RSSs,the complex of RSSs with a fragment of NBD-O-1 can be generated,which can be easily ionized for MS detection in the negative mode.Therefore,the intracellular RSSs can be well detected upon the incubation of He La cells with the probe of NBD-O-1,exhibiting the total RSS levels by the FL imaging and further providing expression of each RSS by enhanced MS detection.Furthermore,the RSSs during ferroptosis in He La cells have been evaluated using the present strategy,demonstrating the potential for ferroptosis examinations.This work has made an unconventional application of a fluorescent probe to enhance the detection of multiple RSSs by MS,providing significant molecular information for addressing the ferroptosis mechanism.展开更多
Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important...Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.展开更多
Infected diabetic wounds represent one of the most severe complications of diabetes mellitus,with complex pathological mechanisms that present significant challenges in clinical management.Ferroptosis,an emerging form...Infected diabetic wounds represent one of the most severe complications of diabetes mellitus,with complex pathological mechanisms that present significant challenges in clinical management.Ferroptosis,an emerging form of iron-dependent programmed cell death driven by excessive lipid peroxidation,plays a critical role in the progression of infected diabetic wounds.This review systematically examines the central mechanisms of ferroptosis in infected diabetic wounds from three key perspectives:dysregulation of iron metabolism,accumulation of lipid peroxidation products,and impairment of the antioxidant defense system.Moreover,it analyzes the impact of ferroptosis on various cell types-fibroblasts,macrophages,vascular endothelial cells,and keratinocytes-during the impaired healing process.Based on these mechanistic insights,the review summarizes recent advances in ferroptosis-targeted therapeutic strategies for wound repair,including ferroptosis inhibitors,cell-based therapies,and innovative hydrogel materials with promising application potential.By integrating current knowledge on the role of ferroptosis in infected diabetic wounds and associated treatment approaches,this article aims to provide new perspectives and a solid theoretical foundation for future research and the comprehensive management of this challenging condition.展开更多
Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study...Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study,bulk RNA sequencing data(GSE47681 and GSE5296)and single-cell RNA sequencing data(GSE162610)were acquired from gene expression databases.We then conducted differential analysis and immune infiltration analysis.Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms.Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes.Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells,confirming the high expression of Atf3 and Piezo1 in these cells.Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide.In a mouse model of T8 spinal cord injury,low-dose cycloheximide treatment was found to improve neurological function,decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase,and increase levels of the anti-inflammatory cytokine arginase 1.Correspondingly,the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia,while the expression of Acsl4 decreased.Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury,identify the key cell types and genes involved in ferroptosis after spinal cord injury,and validate the efficacy of potential drug therapies,pointing to new directions in the treatment of spinal cord injury.展开更多
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 deg...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.展开更多
Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesio...Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.展开更多
Ferroptosis,an iron-dependent form of programmed cell death,has garnered significant attention in tumor research in recent years.Its core characteristics include aberrant accumulation of lipid peroxides and impairment...Ferroptosis,an iron-dependent form of programmed cell death,has garnered significant attention in tumor research in recent years.Its core characteristics include aberrant accumulation of lipid peroxides and impairment of antioxidant defense mechanisms,such as dysfunction of glutathione peroxidase 4.These fea-tures are closely intertwined with the initiation,progression,and therapeutic resistance of hepatocellular carcinoma(HCC).This review presents a systematic overview of the fundamental molecular mechanisms underlying ferroptosis,en-compassing iron metabolism,lipid metabolism,and the antioxidant system.Fur-thermore,it summarizes the potential applications of targeting ferroptosis in liver cancer treatment,including the mechanisms of action of anticancer agents(e.g.,sorafenib)and relevant ferroptosis-related enzymes.Against the backdrop of the growing potential of artificial intelligence(AI)in liver cancer research,various AI-based predictive models for liver cancer are being increasingly developed.On the one hand,this review examines the mechanisms of ferroptosis in HCC to explore novel early detection markers for liver cancer,to provide new insights for the development of AI-based early diagnostic models.On the other hand,it syn-thesizes the current research progress of existing liver cancer predictive models while summarizing key challenges that AI predictive models may encounter in the diagnosis and treatment of HCC.展开更多
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.Ho...Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.展开更多
Zeng N,Ye G,Zheng M,Liu G,Zhang S,Ma S,Xia Z,Zhou Y,Wang S,Xia Q.Discovery and validation of indole nitroolefins as novel covalent GPX4 inhibitors for inducing ferroptosis in urological cancers.Chin J Cancer Res 2025;...Zeng N,Ye G,Zheng M,Liu G,Zhang S,Ma S,Xia Z,Zhou Y,Wang S,Xia Q.Discovery and validation of indole nitroolefins as novel covalent GPX4 inhibitors for inducing ferroptosis in urological cancers.Chin J Cancer Res 2025;37(3):404-416.doi:10.21147/j.issn.1000-9604.2025.03.09.展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe n...Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.展开更多
Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金funded by The National Key Research and Development Program of China,grant number 2022YFF1000202Sichuan Science and Technology Program,grant number 2023NSFSC1940,2021YFYZ0007 and 2024YFNH0025+1 种基金National Natural Science Foundation of China Grants,grant number 32402745China Agriculture Research System of MOF and MARA,grant number CARS-40。
文摘Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well established as a primary mechanism underlying follicular atresia,the potential involvement of ferroptosis,which is an irondependent form of regulated cell death,remains largely unexplored in chickens.Results Using a tamoxifen(TMX)-induced avian model of follicular atresia,we demonstrated that ferroptosis plays a critical role in follicular degeneration.Inhibition of ferroptosis through pharmacological agents significantly restored follicular function,underscoring its potential as a therapeutic target.Notably,we observed a significant upregulation of ubiquitin-specific peptidase 9,X-linked(USP9X)in GCs during atresia.Through comprehensive in vitro and in vivo investigations,we confirmed that USP9X facilitates follicular atresia by promoting ferroptosis in GCs.Mechanistically,USP9X induces ferroptosis by stabilizing Beclin1 through deubiquitination,thereby activating autophagy-dependent ferroptosis.This pathway was effectively suppressed by autophagy inhibitors,emphasizing the essential role of autophagy in USP9X-mediated ferroptosis.Conclusions Our findings provide the evidence that the USP9X-Beclin1 axis regulates autophagy-dependent ferroptosis during avian follicular atresia.These insights reveal novel molecular targets and potential genetic markers for improving reproductive efficiency in chicken breeding programs.
基金supported by the National Natural Science Foundation of China(No.82073520).
文摘The issue of microplastic(MPs)pollution has received increased attention in recent years.Studies have indicated that inhalation of microplastics may result in the cardiovascular harm.However,the specific mechanism remains to be elucidated.In this study,5μm polystyrene microplastics(PS-MPs)were employed to construct in vivo and in vitro exposure models to investigate the potential mechanisms of microplastic-induced cardiac fibrosis.In vivo model of respiratory exposure to MPs,echocardiography observed a decrease in systolic-diastolic function of the mouse heart,and myocardial tissue showed significant mitochondrial morphological abnormalities and myocardial fibrosis.In vitro models also revealed upregulation of fibrosis indicators in human cardiomyocytes AC16 cells.Transcriptome and RT-qPCR assay exposed that ferroptosis-related pathways were significantly gath-ered in the MPs group,with decreased expression of ferroptosis related genes SLC7A11 and GPX4.Liproxstatin-1(Lip-1),a ferroptosis inhibitor,significantly ameliorated MPs-induced cardiomyocyte fibrosis and ferroptosis.We further demonstrated that inhibition of hypoxia-inducible factor𝛼(HIF-𝛼)and oxidative stress ameliorated PS-MPs-induced cardiomyocyte ferroptosis,and thus upregulation of the HIF pathway and oxidative stress may be the upstream mechanism of MPs-induced ferroptosis in myocardial fibrosis.Above all,our study demonstrated that MPs exposure resulted in cardiac fibrosis via the HIF-ROS-SLC7A11/GPX4 signaling pathway.
基金supported by the National Natural Science Foundation of China (Nos.82302355,32371394)Guangdong Basic and Applied Basic Research Foundation (No.2023A1515012628)+1 种基金the Characteristic Innovation Projects of General Colleges and Universities in Guangdong Province (No.2024KTSCX120)the Science and Technology Program of Guangzhou (Nos.2024A04J3324,2024A03J0078)。
文摘Metal ion homeostasis plays a pivotal role in maintaining cellular functions,and its disruption can initiate regulated cell death pathways.Despite its therapeutic potential,metal ion therapy for breast cancer has been hampered by inefficient ion delivery and the intrinsic resistance mechanisms of cancer cells.In this work,a cuproptosis amplifier of copper-telaglenastat coordinate(denoted as Cu-CB) is developed to trigger cell ferroptosis for synergistic breast cancer treatment.Telaglenastat(CB-839),a glutaminase inhibitor,is identified as an effective copper ionophore that facilitates the formation of Cu-CB.Specially,Cu-CB can promote the aggregation of lipoylated proteins to initiate cuproptosis,while also inhibiting glutathione(GSH) synthesis and downregulating glutathione peroxidase 4(GPX4) to trigger ferroptosis.The interplay between these cuproptosis and apoptosis pathways,mediated by Cu-CB,significantly amplifies reactive oxygen species(ROS) production and lipid peroxidation,culminating in the synergistic suppression of breast cancer.Both in vitro and in vivo studies validate the superior antitumor effects of Cu-CB through the induction of cuproptosis and ferroptosis,which may provide a new insight for metal ion delivery systems and metal ion-based tumor therapies.
基金supported by Project of Zhangjiajie City’s Industry-Academia-Research Collaborative Innovation‘Open Project Leader’,Zhangjiajie City’s Project of Taking on Challenging Tasks by Responding to Calls for Solutions(JB20230530)Basic Research Funds Project for Central Universities of China(2023XCZX001,2020kfyXJJS120)Academician and Expert Workstations in Yunnan Province(202205AF150090).
文摘Vine tea is documented in ancient Chinese books as having the function of promoting blood circulation.However,its effects and mechanisms remain unclear.The aim of this study was to comprehensively investigate the protective potential and mechanisms of vine tea in high-fat diet rat through a combination of in vivo and in vitro experiments.The efficacy of vine tea was evaluated using a high-fat diet rat model and an oxidized low-density lipoprotein-treated cell model,with physiological and biochemical indicators measured in rat serum and cell supernatants.Transcriptomics was utilized to investigate alterations mRNA expression following the administration of dihydromyricetin in cell model.Metabolomics and 16S rRNA sequencing was employed to examine changes in metabolites in the serum and changes in gut microbiota of high-fat diet rats after administering vine tea extract.Vine tea extract and dihydromyricetin can reduce elevated levels of lipids,including total cholesterol and triglycerides,following modeling.Transcriptomic data indicate that dihydromyricetin exerts its effects by regulating ferroptosis signaling pathways.Metabolomic analysis demonstrates that the administration of vine tea extract influences the vitamin K cycle and glutathione,thereby alleviating the progression of ferroptosis.Additionally,16S rRNA sequencing reveals that vine tea extract increases Lactobacillaceae in the gut microbiota,which subsequently affects the levels of lysophosphatidylcholine,a major phospholipid component of oxidized low-density lipoprotein in serum.Our results indicate that vine tea can regulate ferroptosis signaling pathways and increase Lactobacillaceae in the gut microbiota,thereby exhibiting cardiovascular protective effects in high-fat diet rats.
基金supported by National Natural Science Foundation(82272695)the Key Program of Natural Science Foundation of Zhejiang Province(LZ23H160004)National Undergraduate Training Program for Innovation and Entrepreneurship,Zhejiang Xinmiao Talents Program,China.
文摘Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidase 4 axis,iron and lipid metabolism chaos,the NAD(P)Hferroptosis suppressor protein 1—ubiquinone axis,and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis.Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins,differing fundamentally from ferroptosis.Both ferroptosis and cuproptosis exhibit dual roles(promote or inhibit)in cancers.And the sensitivity of different cancer types to ferroptosis varies,which may depend on special metabolic signatures(e.g.,E-cadherin loss causes epithelial–mesenchymal transition,making tumors gain resistance to ferroptosis)and expression of antioxidant defense regulators(e.g.,high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive).At present,traditional Chinese herbal medicine,combination therapy,and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis.In this review,we have summarized the core mechanisms of ferroptosis,ferroptosis differences from cuproptosis,its impact on cancers,and its translational implications in cancer therapy,helping readers quickly get the new information and horizons on them.
基金supported by the Department of Education of Guangdong Province (No.2023KTSCX024)the Project of Traditional Chinese Medicine Bureau of Guangdong Province(No.20251091)+3 种基金the Joint Funds of the National Natural Science Foundation of China (No.U22A20368)the Key-Area Research and Development Program of Guangdong Province (No.2020B1111100004)Guangdong Basic and Applied Basic Research Foundation (No.2020B1515130005)Shenzhen Baoan District Science and Technology Innovation Bureau Project(Nos.2022JD226 and 2023JD252)。
文摘Colorectal cancer(CRC), one of the leading causes of cancer-related mortality globally, urgently requires complementary and alternative therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising anticancer strategy. Dendrobium officinale(D. officinale), a renowned traditional Chinese medicinal herb, is widely used in several Asian countries for its nutritional and therapeutic benefits.Although D. officinale has demonstrated anti-tumor effects, the molecular mechanisms underlying its action against CRC remain incompletely characterized. This study aimed to elucidate the role of D. officinale in suppressing CRC through the induction of ferroptosis and its regulatory effects on glutathione peroxidase 4(GPX4), a key suppressor of ferroptosis. In vitro assays were conducted using HCT116 and SW480 CRC cell lines, and in vivo efficacy was evaluated in BALB/c nude mice bearing CRC xenografts. D. officinale significantly reduced CRC cell viability and proliferation in vitro and suppressed tumor growth in vivo. Induction of ferroptosis was evidenced by elevated levels of Fe^(2+), malondialdehyde(MDA), and lipid peroxidation, along with a depleted glutathione/oxidized glutathione disulfide(GSH/GSSG) ratio. Notably, these effects were reversed by ferroptosis inhibitors, including ferrostatin-1(Fer-1) and deferoxamine. Consistently, D. officinale markedly downregulated GPX4 expression. Overexpression of GPX4 rescued D. officinale-induced ferroptosis, whereas GPX4 silencing exacerbated this effect. D. officinale suppresses CRC by triggering GPX4-dependent ferroptosis,providing a novel, naturally derived therapeutic approach. These findings bridge traditional medicine and modern oncology, establishing a foundation for developing targeted CRC treatments.
基金supported by the Academic Leader Training Programof Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13)Shanghai Municipal Health Commission(Grant No.202340094).
文摘Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
基金supported by the National Key Research and Development Program of China (No.2024YFA1509600)National Natural Science Foundation of China (Nos.22474010 and 22274012)the Fundamental Research Funds for the Central Universities (No.2233300007)。
文摘Ferroptosis has exhibited great potential in therapies and intracellular reducing agents of sulfur species(RSSs) in the thiol-dependent redox systems are crucial in ferroptosis.This makes the simultaneous detection of multiple RSSs significant for evaluating ferroptosis therapy.However,the traditional techniques,including fluorescent(FL) imaging and electrospray ionization-based mass spectrometry(MS) detection,cannot achieve the discrimination of different RSSs.Herein,simultaneous MS detection of multiple RSSs,including cysteine(Cys),homocysteine(Hcy),glutathione(GSH) and hydrogen sulfide(H_(2)S),was obtained upon enhancing ionization efficiency by a fluorescent probe(NBD-O-1).Based on the interaction between NBD-O-1 and RSSs,the complex of RSSs with a fragment of NBD-O-1 can be generated,which can be easily ionized for MS detection in the negative mode.Therefore,the intracellular RSSs can be well detected upon the incubation of He La cells with the probe of NBD-O-1,exhibiting the total RSS levels by the FL imaging and further providing expression of each RSS by enhanced MS detection.Furthermore,the RSSs during ferroptosis in He La cells have been evaluated using the present strategy,demonstrating the potential for ferroptosis examinations.This work has made an unconventional application of a fluorescent probe to enhance the detection of multiple RSSs by MS,providing significant molecular information for addressing the ferroptosis mechanism.
基金supported by the Science and Technology Development Plan Project of Jilin Province,No.YDZJ202401157ZYTS(to SL).
文摘Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.
基金supported by the Academician Innovation Platform of Hainan Province,National Natural Science Foundation of China(82560446)Natural Science Foundation of Hainan Province(822MS174),(822RC692)the Science and Technology Special Fund of Hainan Province(ZDYF2025SHFZ049).
文摘Infected diabetic wounds represent one of the most severe complications of diabetes mellitus,with complex pathological mechanisms that present significant challenges in clinical management.Ferroptosis,an emerging form of iron-dependent programmed cell death driven by excessive lipid peroxidation,plays a critical role in the progression of infected diabetic wounds.This review systematically examines the central mechanisms of ferroptosis in infected diabetic wounds from three key perspectives:dysregulation of iron metabolism,accumulation of lipid peroxidation products,and impairment of the antioxidant defense system.Moreover,it analyzes the impact of ferroptosis on various cell types-fibroblasts,macrophages,vascular endothelial cells,and keratinocytes-during the impaired healing process.Based on these mechanistic insights,the review summarizes recent advances in ferroptosis-targeted therapeutic strategies for wound repair,including ferroptosis inhibitors,cell-based therapies,and innovative hydrogel materials with promising application potential.By integrating current knowledge on the role of ferroptosis in infected diabetic wounds and associated treatment approaches,this article aims to provide new perspectives and a solid theoretical foundation for future research and the comprehensive management of this challenging condition.
基金supported by the National Natural Science Foundation of China,No.81972073(to HZ)a grant from the Taishan Scholars Program ofShandong Province-Young Taishan Scholars,No.tsqn201909197(to HZ)+1 种基金a grant from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)a grant from Academic Expert International Innovation Summit,No.22JRRCRC00010(to SF).
文摘Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study,bulk RNA sequencing data(GSE47681 and GSE5296)and single-cell RNA sequencing data(GSE162610)were acquired from gene expression databases.We then conducted differential analysis and immune infiltration analysis.Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms.Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes.Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells,confirming the high expression of Atf3 and Piezo1 in these cells.Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide.In a mouse model of T8 spinal cord injury,low-dose cycloheximide treatment was found to improve neurological function,decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase,and increase levels of the anti-inflammatory cytokine arginase 1.Correspondingly,the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia,while the expression of Acsl4 decreased.Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury,identify the key cell types and genes involved in ferroptosis after spinal cord injury,and validate the efficacy of potential drug therapies,pointing to new directions in the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82171076(to XS)and U22A20311(to XS),82101168(to TL)Shanghai Science and technology Innovation Action Plan,No.23Y11901300(to JS)+1 种基金Science and Technology Commission of Shanghai Municipality,No.21ZR1451500(to TL)Shanghai Pujiang Program,No.22PJ1412200(to BY)。
文摘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.
基金supported by the Qingdao Medical Health Research Project,No.2023-WJZD212(to XX)。
文摘Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.
基金Supported by Henan Provincial Science and Technology Research Project,No.252102311168 and No.242102310066the Medical Education Research Project in Henan Province,No.WJLX2024153.
文摘Ferroptosis,an iron-dependent form of programmed cell death,has garnered significant attention in tumor research in recent years.Its core characteristics include aberrant accumulation of lipid peroxides and impairment of antioxidant defense mechanisms,such as dysfunction of glutathione peroxidase 4.These fea-tures are closely intertwined with the initiation,progression,and therapeutic resistance of hepatocellular carcinoma(HCC).This review presents a systematic overview of the fundamental molecular mechanisms underlying ferroptosis,en-compassing iron metabolism,lipid metabolism,and the antioxidant system.Fur-thermore,it summarizes the potential applications of targeting ferroptosis in liver cancer treatment,including the mechanisms of action of anticancer agents(e.g.,sorafenib)and relevant ferroptosis-related enzymes.Against the backdrop of the growing potential of artificial intelligence(AI)in liver cancer research,various AI-based predictive models for liver cancer are being increasingly developed.On the one hand,this review examines the mechanisms of ferroptosis in HCC to explore novel early detection markers for liver cancer,to provide new insights for the development of AI-based early diagnostic models.On the other hand,it syn-thesizes the current research progress of existing liver cancer predictive models while summarizing key challenges that AI predictive models may encounter in the diagnosis and treatment of HCC.
基金supported by the National Nature Science Foundation of China(NO.82260699)the Science and Technology Leading Talents of Ningxia(NO.2022GKLRLX011)the West Light Foundation of The Chinese Academy of Sciences(the Science and Technology Department of Ningxia,Department of Science and Technology Cooperation[2021]NO.2).
文摘Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer(TNBC)therapy.However,the ferroptosis accompanied with down-regulation of glutathione peroxidase 4(GPX4)lead to CD36-mediated tumor-infiltrating CD8^(+)T cells uptaking fatty acids,resulting in the negative action on immunotherapeutic efficacy.Herein,the albumin nanoparticles,abbreviated as LHS NPs,were designed by co-assembly of hemin,linoleic acid-cystamine,and a CD36 inhibitor sulfosuccinimide oleate,to bi-directionally manipulated ferroptosis in tumor and CD8^(+)T cells for TNBC therapy.LHS NPs exerted more efficient reactive oxygen species generation,glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes,which amplified the positive action on ferroptosis in tumor cells.Meanwhile,LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8^(+)T cells,thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death,proliferation of CD4+CD8^(+)T cells and natural killer cells,alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells,and repolarization of the M2-to M1-phenotype tumor-associated macrophages.Thus,LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lungmetastasis of 4T1-tumormice.Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8^(+)T cells on TNBC chemoimmunotherapy.
文摘Zeng N,Ye G,Zheng M,Liu G,Zhang S,Ma S,Xia Z,Zhou Y,Wang S,Xia Q.Discovery and validation of indole nitroolefins as novel covalent GPX4 inhibitors for inducing ferroptosis in urological cancers.Chin J Cancer Res 2025;37(3):404-416.doi:10.21147/j.issn.1000-9604.2025.03.09.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82071307(to HL),82271362(to HL),82171294(to JW),82371303(to JW),and 82301460(to PX)the Natural Science Foundation of Jiangsu Province,No.BK20211552(to HL)+1 种基金Suzhou Medical Technology Innovation Project-Clinical Frontier,No.SKY2022002(to ZY)the Science and Education Foundation for Health of Suzhou for Youth,No.KJXW2023001(to XL)。
文摘Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
