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

The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions DOI Open Access
Guang Lei, Li Zhuang, Boyi Gan

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(4), P. 513 - 534

Published: April 1, 2024

Language: Английский

Citations

125
Targeting cuproplasia and cuproptosis in cancer DOI
Daolin Tang, Guido Kroemer, Rui Kang

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(5), P. 370 - 388

Published: March 14, 2024

Language: Английский

Citations

116
Oxidative cell death in cancer: mechanisms and therapeutic opportunities DOI Creative Commons
Xiaoqin An, Wenfeng Yu, Jinbao Liu

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)

Published: Aug. 1, 2024

Abstract Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules generated as natural byproducts during cellular processes, including metabolism. Under normal conditions, ROS play crucial roles in diverse functions, cell signaling and immune responses. However, a disturbance the balance between production antioxidant defenses can lead to an excessive buildup, causing oxidative stress. This stress damages essential components, lipids, proteins, DNA, potentially culminating death. form of death take various forms, such ferroptosis, apoptosis, necroptosis, pyroptosis, paraptosis, parthanatos, oxeiptosis, each displaying distinct genetic, biochemical, characteristics. The investigation holds promise for development pharmacological agents that used prevent tumorigenesis or treat established cancer. Specifically, targeting key SLC7A11, GCLC, GPX4, TXN, TXNRD, represents emerging approach inducing cancer cells. review provides comprehensive summary recent progress, opportunities, challenges therapy.

Language: Английский

Citations

73
International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis DOI Creative Commons
Xin Chen,

Andrey S. Tsvetkov,

Han‐Ming Shen

et al.

Autophagy, Journal Year: 2024, Volume and Issue: 20(6), P. 1213 - 1246

Published: March 6, 2024

Macroautophagy/autophagy is a complex degradation process with dual role in cell death that influenced by the types are involved and stressors they exposed to. Ferroptosis an iron-dependent oxidative form of characterized unrestricted lipid peroxidation context heterogeneous plastic mechanisms. Recent studies have shed light on involvement specific autophagy (e.g. ferritinophagy, lipophagy, clockophagy) initiating or executing ferroptotic through selective anti-injury proteins organelles. Conversely, other forms reticulophagy lysophagy) enhance cellular defense against damage. Dysregulated autophagy-dependent ferroptosis has implications for diverse range pathological conditions. This review aims to present updated definition ferroptosis, discuss influential substrates receptors, outline experimental methods, propose guidelines interpreting results.

Language: Английский

Citations

63
Ferroptosis: principles and significance in health and disease DOI Creative Commons
Fangquan Chen, Rui Kang, Daolin Tang

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 6, 2024

Abstract Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic pathway in 2012, ferroptosis has emerged crucial mechanism numerous physiological pathological contexts, leading to significant therapeutic advancements across wide range diseases. This review summarizes the fundamental mechanisms regulatory pathways underlying ferroptosis, including both GPX4-dependent -independent antioxidant mechanisms. Additionally, we examine involvement various conditions, cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, metabolic disorders. Specifically, explore role response chemotherapy, radiotherapy, immunotherapy, nanotherapy, targeted therapy. Furthermore, discuss pharmacological strategies for modulating potential biomarkers monitoring this process. Lastly, elucidate interplay between other forms regulated death. Such insights hold promise advancing our understanding context human health disease.

Language: Английский

Citations

52
Ferroptotic therapy in cancer: benefits, side effects, and risks DOI Creative Commons
Jiandong Diao,

Yuanyuan Jia,

Enyong Dai

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 3, 2024

Abstract Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture intracellular content release. Originally investigated as targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential complement chemotherapy, immunotherapy, radiotherapy in various types. However, it can lead side effects, including immune death, bone marrow impairment, liver kidney damage, cachexia (severe weight loss muscle wasting), secondary tumorigenesis. In this review, we discuss the advantages offer an overview diverse range documented effects. Furthermore, examine underlying mechanisms explore strategies effect mitigation.

Language: Английский

Citations

31
AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer DOI
Changfeng Li, Yuanda Liu, Chang Liu

et al.

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(783)

Published: Jan. 29, 2025

Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is highly selective and first-in-class inhibitor under clinical development. Here, we report that advanced glycosylation end product-specific receptor (AGER) plays key role in mediating resistance PDAC cells. The up-regulation AGER within cancer cells instigates macropinocytosis, facilitating internalization serum albumin subsequent amino acid generation. These acids are then used to synthesize antioxidant glutathione, leading due inhibition apoptosis. underlying molecular mechanism involves AGER's interaction with diaphanous-related formin 1 (DIAPH1), protein responsible for driving Rac family small GTPase (RAC1)-dependent macropinosome formation. effectiveness safety combining pharmacological inhibitors AGER-DIAPH1 complex (using RAGE299) or macropinocytosis EIPA) were confirmed patient-derived xenografts, orthotopic models, genetically engineered mouse models. This combination therapy also induces high-mobility group box (HMGB1) release, resulting antitumor CD8+ T cell response immunocompetent mice. Collectively, study findings underscore potential enhance efficacy blockade targeting AGER-dependent macropinocytosis.

Language: Английский

Citations

3
Targeting GPX4 in ferroptosis and cancer: chemical strategies and challenges DOI
Jiao Liu, Daolin Tang, Rui Kang

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(8), P. 666 - 670

Published: June 12, 2024

Language: Английский

Citations

16
Epigenetic modification of ferroptosis by non-coding RNAs in cancer drug resistance DOI Creative Commons
Hongquan Wang, Joshua S. Fleishman,

Sihang Cheng

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Aug. 27, 2024

Abstract The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, unique type regulated cell death, plays pivotal role inhibiting tumour growth, presenting new opportunities treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine vulnerability to ferroptosis. In this review, we first summarize the growth/development. Then, core molecular mechanisms ferroptosis, its upstream regulation, and downstream effects on Finally, review recent advances understanding how ncRNAs regulate ferroptosis from such modulate This aims enhance general ncRNA-mediated regulatory which highlighting ncRNA-ferroptosis axis as key druggable target overcoming

Language: Английский

Citations

15
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