NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism DOI Creative Commons
Jiao Liu, Hu Tang, Fangquan Chen

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 28, 2024

Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), major non-protein thiol in cells, acts as cuproptosis inhibitor pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits chelating copper, contrasting its role blocking ferroptosis inhibiting lipid peroxidation. The classical inducer, ES-Cu (elesclomol plus copper), increases protein stability transcription factor NFE2L2 (also known NRF2), leading to upregulation gene expression glutamate-cysteine ligase modifier subunit (GCLM) catalytic (GCLC). GCLM GCLC are rate-limiting enzymes synthesis, increased transported into mitochondria via solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression culture mouse models. These findings not only reveal distinct mechanisms ferroptosis, but also suggest potential combination strategy suppress PDAC growth.

Language: Английский

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti‐PD‐1/PD‐L1 cancer immunotherapy DOI Creative Commons
Li Yu, Ke Huang, Yixiang Liao

et al.

Cell Proliferation, Journal Year: 2024, Volume and Issue: 57(8)

Published: April 9, 2024

Abstract Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti‐programmed cell death 1 (PD1) ligand (PD‐L1), have shown clinical efficacy in immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses this treatment. An emerging avenue involves triggering non‐apoptotic regulated (RCD), a significant mechanism driving cancer diverse treatments. Recent research demonstrates that combining RCD inducers with significantly enhances their antitumor across various types. The use anti‐PD‐1/PD‐L1 activates CD8 + T cells, prompting initiation novel forms, such as ferroptosis, pyroptosis, necroptosis. functions mechanisms anti‐PD1/PD‐L1 therapy remain insufficiently explored. This review summarises roles necroptosis It emphasises synergy between nanomaterials PD‐1/PD‐L1 induce different Furthermore, targeting signalling pathways combination therapies holds promise prospective strategy for

Language: Английский

Citations

14
Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis DOI Open Access
Junichi Fujii, Hirotaka Imai

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7544 - 7544

Published: July 9, 2024

Ferroptosis is a type of nonapoptotic cell death that characteristically caused by phospholipid peroxidation promoted radical reactions involving iron. Researchers have identified many the protein factors are encoded genes promote ferroptosis. Glutathione peroxidase 4 (GPX4) key enzyme protects phospholipids from and suppresses ferroptosis in glutathione-dependent manner. Thus, dysregulation involved cysteine and/or glutathione metabolism closely associated with From perspective dynamics, actively proliferating cells more prone to than quiescent cells, which suggests species generated during oxygen-involved responsible for lipid peroxidation. Herein, we discuss initial events dominantly occur process energy metabolism, association deficiency. Accordingly, tricarboxylic acid cycle coupled respiratory chain mitochondria main subjects here, this likely source both electrons free Since not only carbohydrates, but also amino acids, especially glutamate, major substrates central dealing nitrogen derived groups contributes subject discussion.

Language: Английский

Citations

14
Induction of ferroptosis: A new strategy for the control of bacterial infections DOI
Rongxian Guo, Xin Fang, Ke Shang

et al.

Microbiological Research, Journal Year: 2024, Volume and Issue: 284, P. 127728 - 127728

Published: April 17, 2024

Language: Английский

Citations

9
Dual‐Release Free Iron and Breakdown of Ferroptosis Defenses to Achieve Ferroptosis Cascade Storms for Potent Antitumor Therapy DOI Open Access

Wenting Xu,

Yuzhen Yang, Lijuan Liu

et al.

Advanced Functional Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 19, 2025

Abstract Ferroptosis is a newly identified type of regulated cell death characterized by iron‐dependent lipid peroxidation. Among the main ferroptosis‐suppressing systems, dihydroorotate dehydrogenase (DHODH)‐ ubiquinone axis closely related to mitochondria and energy metabolism, implying that protects cells from oxidative stress damage via maintenance redox homeostasis. However, ferroptosis initiation requires suitable environment breakthrough in homeostatic limitations systems. Hence, nanoparticles are rationally engineered achieve efficient induction releasing dual‐release free iron disrupting Atovaquone (ATO)‐loaded hollow mesoporous etching zeolitic imidazolate framework‐67 double‐coated oxide/calcium phosphate (Fe 3 O 4 /CaP) conjugated with polyethylene glycol. The external Fe /CaP structure enhances efficiency multiple reactive oxygen species (ROS) generation promoting stress. Still, it achieves increase content unstable pools for igniting ROS storm peroxidation spark. release ATO not only affects metabolism mitochondrial respiratory chain binding complex III but also downregulates DHODH restrict ubiquinol system disrupt Therefore, design this composite nanomedicine provides an approach inducing theoretical basis clinical anti‐tumor trials.

Language: Английский

Citations

1
MiR-370-3p regulate TLR4/SLC7A11/GPX4 to alleviate the progression of glucocorticoids-induced osteonecrosis of the femoral head by promoting osteogenesis and suppressing ferroptosis DOI Creative Commons

Rongtai Zuo,

Bojun Cao, Lingchi Kong

et al.

Journal of Orthopaedic Translation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Redox Imbalance Drives Magnetic Property and Function Changes in Mice DOI Creative Commons
Chuanlin Feng, Lei Zhang, Xiaoyuan Zhou

et al.

Redox Biology, Journal Year: 2025, Volume and Issue: 81, P. 103561 - 103561

Published: Feb. 21, 2025

Language: Английский

Citations

1
Functional nanozyme system for synergistic tumor immunotherapy via cuproptosis and ferroptosis activation DOI Creative Commons

Lina Gu,

Ying Sun,

Tingjie Bai

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 15, 2025

Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death subsequent antitumor immune responses. However, dysregulated metabolism in cells maintains homeostatic balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed CussOMEp, comprising copper-based nanovector (CussNV) that is PEGylated loaded with omeprazole, transporter inhibitor, enhance synergistic immunotherapy by promoting ferroptosis. CussNV assembled from dithiodiglycolic acid ions, exhibiting peroxidase, glutathione oxidase, catalase-like activities, along responsive degradability. This alleviates hypoxia producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, depletes glutathione. Additionally, omeprazole increases cellular concentration oxidative stress inhibiting intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization cuproptosis. breast mouse model, CussOMEp elicits robust responses, including dendritic maturation T proliferation. When combined PD-1 antibodies (αPD-1), significantly inhibits metastasis bilateral lung metastatic models. work presents functional system as promising strategy for leveraging

Language: Английский

Citations

1
Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation DOI
Hai‐Liang Zhang, Yi-Qing Guo, Shan Liu

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Language: Английский

Citations

1
Alkaliptosis induction counteracts paclitaxel‐resistant ovarian cancer cells via ATP6V0D1‐mediated ABCB1 inhibition DOI
Fangquan Chen, Junhao Lin, Rui Kang

et al.

Molecular Carcinogenesis, Journal Year: 2024, Volume and Issue: 63(8), P. 1515 - 1527

Published: May 15, 2024

Abstract Paclitaxel serves as the cornerstone chemotherapy for ovarian cancer, yet its prolonged administration frequently culminates in drug resistance, presenting a substantial challenge. Here we reported that inducing alkaliptosis, rather than apoptosis or ferroptosis, effectively overcomes paclitaxel resistance. Mechanistically, ATPase H + transporting V0 subunit D1 (ATP6V0D1), key regulator of plays pivotal role by mediating downregulation ATP‐binding cassette subfamily B member 1 (ABCB1), multidrug resistance protein. Both ATP6V0D1 overexpression through gene transfection and pharmacological enhancement protein stability using JTC801 inhibit ABCB1 upregulation, resulting growth inhibition drug‐resistant cells. Additionally, increasing intracellular pH to alkaline (pH 8.5) via sodium hydroxide application suppresses expression, whereas reducing acidic conditions 6.5) with hydrochloric acid amplifies expression Collectively, these results indicate potentially effective therapeutic strategy targeting paclitaxel‐resistant cancer ATP6V0D1‐dependent alkaliptosis.

Language: Английский

Citations

8
NFE2L2 and ferroptosis resistance in cancer therapy DOI Open Access
Daolin Tang, Rui Kang

Cancer Drug Resistance, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

NFE2-like basic leucine zipper transcription factor 2 (NFE2L2, also known as NRF2), is a key in the cellular defense against oxidative stress, playing crucial role cancer cell survival and resistance to therapies. This review outlines current knowledge on link between NFE2L2 ferroptosis - form of regulated death characterized by iron-dependent lipid peroxidation within cells. While activation can protect normal cells from damage, its overexpression contributes drug upregulating antioxidant defenses inhibiting ferroptosis. We delve into molecular pathways ferroptosis, highlighting involvement target genes, such

Language: Английский

Citations

8