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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Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 22, 2024

Abstract Cancer-associated fibroblasts (CAFs), the main stromal component of tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms regulated death (RCD) adjacent cells, thus involving proliferation, therapy resistance, immune exclusion. Here, we present a brief introduction to basic knowledge RCD, including apoptosis, autophagy, ferroptosis, pyroptosis. In addition, further summarize different types RCD tumors are mediated by CAFs, as well effects these modes on CAFs. This review will deepen our understanding interactions between might offer novel therapeutic avenues for future treatments.

Language: Английский

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The crosstalk between immune cells and tumor pyroptosis: advancing cancer immunotherapy strategies

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: July 10, 2024

Abstract Pyroptosis is a cell death process characterized by swelling until membrane rupture and release of intracellular contents. As an effective tumor treatment strategy, inducing pyroptosis has received widespread attention. In this process, the immune components within microenvironment play key regulatory role. By regulating altering functions cells such as cytotoxic T lymphocytes, natural killer cells, tumor-associated macrophages, neutrophils, can be induced. This article provides comprehensive review molecular mechanisms pyroptosis, impact on its mechanisms. It aims to gain in-depth understanding communication between provide theoretical support for development new immunotherapies.

Language: Английский

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Copper‐Based Bio‐Coordination Nanoparticle for Enhanced Pyroptosis‐Cuproptosis Cancer Immunotherapy through Redox Modulation and Glycolysis Inhibition

Small, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability induce oxidative stress and cuproptosis cells. However, antitumor effectiveness is constrained by the dynamic redox balance metabolic shift between phosphorylation glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) designed for combined pyroptosis-cuproptosis immunotherapy amplifying reactive oxygen species (ROS) production regulating cellular metabolism. The intracellular imbalance achieved through synergistic effects of α-KG-induced mitochondrial reprogramming, photothermally enhanced superoxide dismutase-like activity polydopamine, glutathione depletion copper ions. multifaceted modulation results substantial increase ROS levels, triggering subsequent pyroptosis Furthermore, α-KG shifts metabolism from glycolysis phosphorylation, thereby enhancing induced combination dyshomeostasis inhibition potent enhancement pyroptosis-cuproptosis-mediated therapy. In murine model colorectal cancer, CKPP exhibited remarkable anticancer effect, achieving tumor rate 96.3% complete eradication two out five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates potential treating immunotherapy.

Language: Английский

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Ferroptosis in Non-Small Cell Lung Cancer: Progression and Therapeutic Potential on It

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(24), P. 13335 - 13335

Published: Dec. 11, 2021

As a main subtype of lung cancer, the current situation non-small cell cancer (NSCLC) remains severe worldwide with 19% survival rate at 5 years. conventional therapy approaches, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, gradually develop into resistance, searching for novel therapeutic strategy NSCLC is urgent. Ferroptosis, an iron-dependent programmed necrosis, has now been widely considered key factor affecting tumorigenesis progression in various cancers. Focusing on its effect NSCLC, different situations, ferroptosis can be triggered or restrained. When was induced it available to inhibit tumor both vitro vivo. The dominating mechanism due regulation classic ferroptosis-repressed GSH-dependent GPX4 signaling pathway instead other fractional regulating signal axes that regulated via impacting ROS, cellular iron levels, etc. In terms prevention GSH-independent also discovered, interestingly exhibiting same upstream signaling. addition, this review summarizes elaborates their association specific mechanisms through bioinformatics analysis multiple experimental evidence from cascades. Finally, points out possibility working resistance emphasizing potential.

Language: Английский

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Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Sept. 14, 2022

Abstract Regulated cell death (RCD) is a critical and active process that controlled by specific signal transduction pathways can be regulated genetic signals or drug interventions. Meanwhile, RCD closely related to the occurrence therapy of multiple human cancers. Generally, subroutines are key tumorigenesis, which contributed our better understanding cancer pathogenesis therapeutics. Indole alkaloids derived from natural sources well defined for their outstanding biological pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, 3,3′-diindolylmethane, currently used in clinic under clinical assessment. Moreover, such compounds play significant role discovering novel anticancer agents. Thus, here we systemically summarized recent advances indole as agents targeting different subroutines, including classical apoptosis autophagic signaling crucial other ferroptosis, mitotic catastrophe, necroptosis, anoikis, cancer. further discussed cross talk between mediated combined strategies (e.g., 3,10-dibromofascaplysin with olaparib) exhibit therapeutic potential against various cancers regulating subroutines. In short, information provided this review on regulation targets expected beneficial design molecules greater thereby facilitating development new therapy. Graphic abstract

Language: Английский

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Knowledge Mapping of Necroptosis From 2012 to 2021: A Bibliometric Analysis

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

Published: June 13, 2022

Necroptosis, a recently discovered programmed cell death, has been pathologically linked to various diseases and is thus promising target for treating diseases. However, comprehensive objective report on the current status of entire necroptosis research lacking. Therefore, this study aims conduct bibliometric analysis quantify identify quo trending issues in last decade.Articles were acquired from Web Science Core Collection database. We used two tools (CiteSpace VOSviewer) individual impact cooperation information by analyzing annual publications, journals, co-cited countries/regions, institutions, authors, authors. Afterwards, we identified areas co-occurrence burst keywords references.From 2012 2021, total 3,111 articles published 786 academic journals 19,687 authors 885 institutions 82 countries/regions. The majority publications China United States, which States maintained dominant position research; meanwhile, Chinese Academy Sciences Ghent University most active institutions. Peter Vandenabeele papers, while Alexei Degterev had co-citations. Cell Death & Disease papers necroptosis, was top 1 journal, major area these molecular, biology, immunology. High-frequency mainly included those that are molecularly related (MLKL, TNF-alpha, NF-κB, RIPK3, RIPK1), pathological process (cell-death, apoptosis, necrosis, inflammation), disease (cancer, ischemia/reperfusion injury, infection, carcinoma, Alzheimer's disease).Necroptosis stable stepwise growth past decade. Current studies focused its cross-talk with other types potential applications treatment, further mechanisms. Among them, synergy ferroptosis, RIPK1/RIPK3/MLKL studies, association inflammation oxidative stress translational applications, therapeutic treat cancer neurodegenerative area. These might provide ideas field.

Language: Английский

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Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 193, P. 202 - 212

Published: Oct. 10, 2022

Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation lipid peroxides to lethal levels, which morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, pyroptosis. Manganese play an important role in innate immunity antitumor immunity. Many manganese-based nanomaterials induce tumor catalyzing production reactive oxygen species (ROS) within tumor. However, exact underlying mechanisms remain unclear. As research on ferroptosis advances its regulatory tumors continue be refined, more evidence has suggested that triggering cells effective strategy for treatment. In this study, we found administration MnCl2 resulted peroxidation increased levels mitochondrial ROS, consequently leading ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated defence targetable vulnerability cancer. We show downregulated DHODH expression cells, resulting ROS addition, enhanced phosphorylation STING, TBK1, IRF3 upregulated type-I interferon (IFN), produced cGAS-STING signaling pathway. When inhibiting pathway or IFN, was restored, reversing rescuing MnCl2-induced ferroptosis.. Knockout IFNAR1 overexpression weakens effect MnCl2. Mechanistically, these results revealed treatment-activated promote releasing IFNs reduce function thereby inducing cells. This may provide new complement existing treatment regimens.

Language: Английский

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Ferroptosis: At the Crossroad of Gemcitabine Resistance and Tumorigenesis in Pancreatic Cancer

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(20), P. 10944 - 10944

Published: Oct. 10, 2021

The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because resistance to all known therapies, including chemotherapeutic drugs. In decades, gemcitabine been at forefront treatment for ductal adenocarcinoma, but more strategies combat drug need be explored. One promising possibility is ferroptosis, a form nonapoptotic cell death that depends on intracellular iron and occurs through accumulation lipid reactive oxygen species, which are significant resistance. this article, we reviewed gemcitabine-resistance mechanisms; assessed relationship among tumorigenesis resistance, explored new method cancer.

Language: Английский

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Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis

Autophagy, Journal Year: 2022, Volume and Issue: 19(6), P. 1733 - 1744

Published: Nov. 25, 2022

5-HETE, 5-hydroxyeicosatetraenoic acid; ACSL4, acyl-CoA synthetase long chain family member 4; AP, acute pancreatitis; ATG, autophagy related; AGER, advanced glycosylation end-product specific receptor; DAMPs, danger/damage-associated molecular patterns; FTH1, ferritin heavy 1; GPX4, glutathione peroxidase IL, interleukin; INSR, insulin MAP1LC3B, microtubule associated protein 1 light 3 beta; MDA, malondialdehyde; MPO, myeloperoxidase; PRRs, pattern recognition receptors; PUFA, polyunsaturated fatty RNAi, RNA interference; SQSTM1, sequestosome TNF, tumor necrosis factor; TLR, toll like receptor.

Language: Английский

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