TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling

JHEP Reports, Journal Year: 2023, Volume and Issue: 5(5), P. 100695 - 100695

Published: Feb. 3, 2023

Oxidative stress-mediated ferroptosis and macrophage-related inflammation play an important role in various liver diseases. Here, we explored if how hepatocyte regulates macrophage stimulator of interferon genes (STING) activation the development spontaneous damage, fibrosis, tumorigenesis.We used a transforming growth factor-beta-activated kinase 1 (TAK1) deficiency-induced model tumorigenesis to investigate its impact on STING signalling. Primary hepatocytes macrophages were for vitro experiments.Significant injury increased numbers intrahepatic M1 found hepatocyte-specific TAK1-deficient (TAK1ΔHEP) mice, peaking at 4 weeks gradually decreasing 8 12 weeks. Meanwhile, signalling was observed livers from TAK1ΔHEP mice had decreased Treatment with inhibitor promoted M2 polarisation alleviated injury, tumour burden. TAK1 deficiency exacerbated iron metabolism high-iron diet. Moreover, consistent results single-cell RNA-Seq dataset, demonstrated oxidative response hepatocellular ferroptosis, which could be inhibited by reactive oxygen species scavenging. Suppression ferrostatin-1 signalling, leading attenuated fibrosis reduced Mechanistically, serum levels 8-hydroxydeoxyguanosine detected suppressed inhibition. antibody mice.Hepatocellular ferroptosis-derived DNA damage promotes facilitate tumorigenesis. Inhibition may represent novel therapeutic approach prevention chronic disease.The precise mechanism progression remains unclear. Herein, show that deletion caused carcinoma.

Language: Английский

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STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 208, P. 348 - 360

Published: Aug. 26, 2023

Ferroptosis in tubules has been implicated the pathogenesis of acute kidney injury (AKI), whereas regulatory mechanism remains unclear. The stimulator interferon genes (STING) is previously recognized as a critical mediator innate immunity via DNA-sensing pathway and increasingly linked to lipid peroxidation, hallmark ferroptosis. Herein we investigated role underlying STING AKI models established by ischemia/reperfusion (IR) C57BL mice. expression level was predominantly increased after IR treatment. Besides, deficiency markedly alleviated IR-induced tissue damage renal dysfunction. Consistently, vitro experiments demonstrated that increase ferroptotic cell death, ROS production decrease GSH peroxidase 4 (GPX4) tubular cells subjected ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated genetic pharmacological inhibition STING, while exacerbated overexpression. Further, these detrimental effects overexpression relied on induction ferritinophagy, i.e. autophagic degradation ferritin, leading iron overload. Mechanistically, mediated initiation ferritinophagy through interacting with nuclear receptor coactivator (NCOA4), fundamental for transfer ferritin into lysosome. Collectively, contributes during ischemic facilitating NCOA4-mediated shows potential promising therapeutic choice AKI.

Language: Английский

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STING orchestrates the neuronal inflammatory stress response in multiple sclerosis

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 4043 - 4060.e30

Published: June 14, 2024

Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce stimulator interferon genes (STING). However, activation STING requires detachment from stromal interaction molecule 1 (STIM1), process triggered by glutamate excitotoxicity. This initiates non-canonical signaling, which leads to autophagic degradation glutathione peroxidase 4 (GPX4), essential for redox homeostasis thereby inducing ferroptosis. Both genetic pharmacological interventions target protect against inflammation-induced neurodegeneration. Our findings position as central regulator detrimental integrating inflammation with signaling cause cell death, present it tractable treating MS.

Language: Английский

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Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis

Journal of Extracellular Vesicles, Journal Year: 2024, Volume and Issue: 13(2)

Published: Feb. 1, 2024

Extracellular vesicles (EVs) exert a significant influence not only on the pathogenesis of diseases but also their therapeutic interventions, contingent upon variances observed in originating cells. Mitochondria can be transported between cells via EVs to promote pathological changes. In this study, we found that derived from M1 macrophages (M1-EVs), which encapsulate inflammatory mitochondria, penetrate pancreatic beta Inflammatory mitochondria fuse with cells, resulting lipid peroxidation and mitochondrial disruption. Furthermore, fragments DNA (mtDNA) are released into cytosol, activating STING pathway ultimately inducing apoptosis. The potential adipose-derived stem cell (ADSC)-released suppressing macrophage reactions shows promise. Subsequently, ADSC-EVs were utilized modified an F4/80 antibody specifically target macrophages, aiming treat ferroptosis vivo. summary, our data further demonstrate secreted phenotype play major roles ferroptosis, exhibit considerable for development as vehicle targeted delivery macrophages.

Language: Английский

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Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps

Burns & Trauma, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 1, 2024

Abstract Background Ensuring the survival of distal end a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention programmed cell death potential strategy for inhibiting ischaemic necrosis. The activation stimulator interferon genes (STING) pathway promotes inflammation and leads to death. epidermal growth factor family member neuregulin-1 (NRG1) reduces by activating protein kinase B (AKT) signalling pathway. Moreover, AKT negatively regulates STING activity. We aimed verify efficacy NRG1 injection protecting against Additionally, we investigated whether effectively enhances ischemic pyroptosis necroptosis through suppression. Methods A random-pattern skin model was generated on backs C57BL/6 mice. area determined. blood supply vascular network assessed laser Doppler flow analysis. Cluster differentiation 34 immunohistochemistry (IHC) haematoxylin eosin (H&E) staining sections revealed microvessels. Transcriptome sequencing analysis mechanism which flaps. levels angiogenesis, oxidative stress, necroptosis, indicators associated with pathways flaps were examined IHC, immunofluorescence Western blotting. Packaging adeno-associated virus (AAV) used activate Results promoted An increased subcutaneous neovascularization found after application NRG1. Transcriptomic gene ontology enrichment level detection indicated that activity reduced group. phosphorylation forkhead box O3a (FOXO3a) treatment. expression induced AAV reversed therapeutic effect ability phosphorylate AKT-FOXO3a, inhibit promote abolished inhibitor MK2206. Conclusions inhibits AKT-FOXO3a suppress survival.

Language: Английский

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Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 17, 2025

Drug resistance is a common challenge in clinical tumor treatment. A reduction drug sensitivity of cells often accompanied by an increase autophagy levels, leading to autophagy-related resistance. The effectiveness combining chemotherapy drugs with inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected various types autophagy. Therefore, ferroptosis have crosstalk via autophagy, potentially switch cell death under certain conditions. As two forms inflammatory programmed death, different effects on inflammation, cGAS-STING signaling pathway also involved. it plays important role progression some chronic diseases. This review discusses relationship between pyroptosis, attempts uncover reasons behind evasion nature

Language: Английский

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Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 28, 2022

Breast cancer is one of the top-ranked malignant carcinomas associated with morbidity and mortality in women worldwide. Chemotherapy main approaches to breast treatment. initially responds traditional first- second-line drugs (aromatase inhibitor, tamoxifen, carboplatin), but eventually acquires resistance, certain patients relapse within 5 years. Chemotherapeutic also have obvious toxic effects. In recent years, natural products been widely used research because their low side effects, toxicity, good efficacy based on multitarget therapy. Apoptosis, a programmed cell death, occurs as normal controlled process that promotes growth death. Inducing apoptosis an important strategy control excessive proliferation. Accumulating evidence has revealed become increasingly treatment by suppressing apoptosis. this study, we reviewed current studies product-induced summarized proapoptosis mechanisms including mitochondrial, FasL/Fas, PI3K/AKT, reactive oxygen species, mitogen-activated protein kinase-mediated pathway. We hope our review can provide direction search for candidate derived from treat promoting

Language: Английский

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Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 25, 2022

Ovarian cancer (OC) is one of the most common malignancies that causes death in women and a heterogeneous disease with complex molecular genetic changes. Because relatively high recurrence rate OC, it crucial to understand associated mechanisms drug resistance discover potential target for rational targeted therapy. Cell genetically determined process. Active orderly cell prevalent during development living organisms plays critical role regulating life homeostasis. Ferroptosis, novel type discovered recent years, distinct from apoptosis necrosis mainly caused by imbalance between production degradation intracellular lipid reactive oxygen species triggered increased iron content. Necroptosis regulated non-cysteine protease–dependent programmed necrosis, morphologically exhibiting same features as occurring via unique mechanism different apoptotic signaling pathway. Pyroptosis form characterized formation membrane pores subsequent lysis well release pro-inflammatory contents mediated abscisin family. Studies have shown ferroptosis, necroptosis, pyroptosis are involved progression variety diseases, including tumors. In this review, we summarized advances occurrence, development, therapeutic OC.

Language: Английский

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NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Sept. 6, 2022

Abstract Emerging evidence suggests that pyroptosis is involved in sepsis. However, the role of neutrophil sepsis and mechanisms remains elusive. We find N-acetyltransferase 10 (NAT10), an acetyltransferase responsible for N 4 -acetylation Cytidine (ac C) mRNA, significantly downregulated neutrophils from septic mice. Neutrophil-specific over-expression NAT10 improves survival ameliorates lung injury mice by inhibiting pyroptosis. Notably, UNC-52-like kinase 1 (ULK1) identified as target neutrophils. The decreased expression resultes decay ULK1 transcripts therefore reduced ULK1. As a regulator STING phosphorylation, loss enhances activation STING-IRF3 signaling subsequently elevated pyroptosis-inducing NLRP3 inflammasome While restrains well lethality reversing ULK1-STING-NLRP3 axis. are also observed patients its correlation with clinical severity found. Collectively, our findings disclose negative downregulation contributes to progress exacerbating via axis, revealing potential therapeutic

Language: Английский

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SARS‐CoV‐2 ORF3a inhibits cGAS‐STING‐mediated autophagy flux and antiviral function

Journal of Medical Virology, Journal Year: 2022, Volume and Issue: 95(1)

Published: Sept. 27, 2022

Abstract Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS‐STING‐mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS‐CoV‐2 infection, responsible COVID‐19 pandemic, triggers cGAS‐STING activation. activation can trigger IRF3‐Type I interferon (IFN) autophagy‐mediated antiviral activity. Although viral evasion of STING‐triggered IFN‐mediated function has been well studied, concerning are scarce. In present study, we discovered ORF3a a unique protein interact with STING disrupt STING‐LC3 interaction, thus blocking cGAS‐STING‐induced autophagy but not IFN induction. This novel ORF3a, distinct from targeting autophagosome‐lysosome fusion, selective inhibition to facilitate replication. We also found bat induce activity despite its defect in Furthermore, coronaviruses block function. Interestingly, ability inhibit STING‐induced appears be an acquired since SARS‐CoV lacks this Taken together, these discoveries identify as potential target intervention COVID‐19.

Language: Английский

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