The multifaceted role of ferroptosis in liver disease

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(3), P. 467 - 480

Published: Jan. 24, 2022

Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora pathological conditions in the liver. Emerging evidence supports notion that dysregulated metabolic pathways impaired iron homeostasis play role progression liver disease via ferroptosis. Although molecular mechanisms which ferroptosis causes are poorly understood, several ferroptosis-associated genes have been implicated disease. Here, we review physiological processing nutrients, our current understanding metabolism, characteristics ferroptosis, regulate In addition, summarize pathogenesis disease, including injury, non-alcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma. Finally, discuss therapeutic potential targeting for managing

Language: Английский

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Signaling pathways and defense mechanisms of ferroptosis

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(22), P. 7038 - 7050

Published: June 6, 2021

As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs develops because sophisticated signals regulatory mechanisms. The reactive oxygen species (ROS) used to initiate come from variety sources, including iron‐mediated Fenton reactions, mitochondrial ROS, membrane‐associated ROS the NOX protein family. Polyunsaturated fatty acid‐containing phospholipids are main substrates in ferroptosis, which is positively regulated enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation autophagic degradation pathways promotes increasing iron accumulation cause peroxidation. In contrast, system xc – ‐glutathione–GPX4 axis plays central role limiting peroxidation, although other antioxidants (such coenzyme Q10 tetrahydrobiopterin) can also inhibit ferroptosis. A nuclear mechanism defense against NFE2L2‐dependent antioxidant response transcriptionally upregulating expression cytoprotective genes. Additionally, damage caused ferroptotic stimulus be repaired ESCRT‐III‐dependent scission machinery. this review, we summarize recent progress understanding signaling mechanisms

Language: Английский

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Ferroptosis in cancer and cancer immunotherapy

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(2), P. 88 - 116

Published: Feb. 1, 2022

Abstract The hallmark of tumorigenesis is the successful circumvention cell death regulation for achieving unlimited replication and immortality. Ferroptosis a newly identified type dependent on lipid peroxidation which differs from classical programmed in terms morphology, physiology biochemistry. broad spectrum injury tumor tolerance are main reasons radiotherapy chemotherapy failure. effective rate immunotherapy as new treatment method less than 30%. can be seen radiotherapy, chemotherapy, immunotherapy; therefore, ferroptosis activation may potential strategy to overcome drug resistance mechanism traditional cancer treatments. In this review, characteristics causes by briefly described. addition, three metabolic regulations its crosstalk with signaling pathways summarized. Collectively, these findings suggest vital role based interaction immunotherapy, thus, indicating remarkable treatment.

Language: Английский

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Copper-dependent autophagic degradation of GPX4 drives ferroptosis

Autophagy, Journal Year: 2023, Volume and Issue: 19(7), P. 1982 - 1996

Published: Jan. 9, 2023

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays master role in blocking ferroptosis eliminating phospholipid hydroperoxides, the regulation remains poorly understood. Here, we report an unexpected for copper promoting ferroptotic death, but not cuproptosis, inducing macroautophagic/autophagic degradation GPX4. Copper chelators reduce sensitivity do inhibit other types such as apoptosis, necroptosis, alkaliptosis. Conversely, exogenous increases ubiquitination formation aggregates directly binding to protein cysteines C107 C148. TAX1BP1 (Tax1 1) then acts autophagic receptor subsequent response stress. Consequently, enhances ferroptosis-mediated tumor suppression mouse model pancreatic cancer tumor, whereas attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into link between metal stress autophagy-dependent death.Abbreviations: CALCOCO2, calcium coiled-coil domain 2; GPX4, glutathione 4; MAP1LC3A/B, microtubule 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear coactivator OPTN, optineurin; PDAC, ductal adenocarcinoma; RIPK1, interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member SQSTM1, sequestosome TAX1BP1, Tax1 TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.

Language: Английский

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Organelle-specific regulation of ferroptosis

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(10), P. 2843 - 2856

Published: Aug. 31, 2021

Language: Английский

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Cell death in pancreatic cancer: from pathogenesis to therapy

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(11), P. 804 - 823

Published: July 30, 2021

Language: Английский

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GPX4 in cell death, autophagy, and disease

Autophagy, Journal Year: 2023, Volume and Issue: 19(10), P. 2621 - 2638

Published: June 4, 2023

Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in use of a reducing agent scavenging lipid peroxidation products. There are three isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development adult life. In addition to inducing phenotype ferroptosis, loss can some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates accelerates developmental defects, tissue damage, sterile inflammation. The interaction autophagic degradation pathway further modulates cell fate response oxidative stress. Impaired function implicated tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, ischemia-reperfusion injury. Additionally, R152H mutation promote Sedaghatian-type spinal metaphyseal dysplasia, rare fatal disease newborns. Here, we discuss roles classical functions well emerging GPX4-regulated processes death, autophagy, disease.Abbreviations: AA: arachidonic acid; cGPX4: GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: nGPX4: GSDMD-N: N-terminal fragment GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated death; ROS: reactive oxygen species; Se: selenium; SSMD: spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system

Language: Английский

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The interaction between ferroptosis and inflammatory signaling pathways

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 21, 2023

Abstract Ferroptosis is an iron-dependent regulated cell death driven by excessive lipid peroxidation. Inflammation one common and effective physiological event that protects against various stimuli to maintain tissue homeostasis. However, the dysregulation of inflammatory responses can cause imbalance immune system, dysfunction death. Recent studies have pointed out activation inflammation, including multiple inflammation-related signaling pathways, lead ferroptosis. Among related signal transduction we focused on five classical namely, JAK-STAT, NF-κB, inflammasome, cGAS-STING MAPK expounded their roles in To date, many agents shown therapeutic effects ferroptosis-related diseases modulating aforementioned pathways vivo vitro. Moreover, regulatory these iron metabolism peroxidation been described detail, contributing further understanding pathophysiological process Taken together, targeting inflammation will provide appropriate ways intervene ferroptosis diseases.

Language: Английский

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Overcoming cancer chemotherapy resistance by the induction of ferroptosis

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 66, P. 100916 - 100916

Published: Dec. 29, 2022

Language: Английский

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Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade

Gut, Journal Year: 2023, Volume and Issue: 72(9), P. 1774 - 1782

Published: Jan. 27, 2023

Investigating the effect of ferroptosis in tumour microenvironment to identify combinatory therapy for liver cancer treatment.Glutathione peroxidase 4 (GPx4), which is considered master regulator ferroptosis, was genetically altered murine models hepatocellular carcinoma (HCC) and colorectal (CRC) analyse on cells immune microenvironment. The findings served as foundation identification additional targets combine with ferroptotic inducer treatment HCC metastasis.Surprisingly, hepatocyte-restricted GPx4 loss does not suppress tumourigenesis. Instead, GPx4-associated hepatocyte death causes a suppressive response characterised by CXCL10-dependent infiltration cytotoxic CD8+ T that counterbalanced PD-L1 upregulation well marked HMGB1-mediated myeloid derived suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1 unleashes activation prolongs survival mice Gpx4-deficient tumours. A triple combination inducing natural compound withaferin A, CXCR2 inhibitor SB225002 α-PD-1 greatly improves wild-type In contrast, same affect growth subcutaneously grown CRC organoids, while it decreases their metastatic liver.Our data highlight context-specific ferroptosis-induced could be therapeutically exploited primary tumours metastases.

Language: Английский

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