Prognostic iron-metabolism signature robustly stratifies single-cell characteristics of hepatocellular carcinoma DOI Creative Commons
Zhipeng Zhu, Cao Huang, Hongyu Yan

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 929 - 941

Published: Feb. 1, 2024

Cancer immunotherapy has shown to be a promising method in treating hepatocellular carcinoma (HCC), but suboptimal responses patients are attributed the cellular and molecular heterogeneity. Iron metabolism-related genes (IRGs) important maintaining immune system homeostasis have potential help developed new strategies for HCC treatment. Herein, we constructed validated iron-metabolism gene prognostic index (IPX) using univariate cox proportional hazards regression LASSO analysis, successfully categorizing into two groups with distinct survival risk. Then, performed single-sample set enrichment weighted correlation network ontology lineage analysis SCENIC reveal key determinants underlying ability of this model based on bulk single-cell transcriptomic data. We identified several driver transcription factors specifically activated specific malignant cell sub-populations contribute adverse outcomes IPX-high subgroup. Within tumor microenvironment (TME), T cells displayed significant diversity their characteristics experienced changes developmental paths within clusters by IPX. Interestingly, proportion Treg was increased high-risk group compared low-risk group. These results suggest that could involved reshaping TME, thereby disrupting cycle cells. This study utilized IRGs construct novel reliable model, which can used assessing prognosis further clarified mechanisms at resolution.

Language: Английский

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer DOI Creative Commons
Jaewang Lee, Jong‐Lyel Roh

Antioxidants, Journal Year: 2022, Volume and Issue: 11(12), P. 2444 - 2444

Published: Dec. 11, 2022

SLC7A11 is a cell transmembrane protein composing the light chain of system xc-, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. critical gateway redox homeostasis by maintaining cellular levels that counter oxidative stress suppress ferroptosis. overexpressed in various human cancers regulates tumor development, proliferation, metastasis, microenvironment, treatment resistance. Upregulation needed to adapt high microenvironments maintain homeostasis. High basal ROS dependences cancer render them vulnerable further stress. Therefore, cyst(e)ine depletion may be an effective new strategy treatment. However, effectiveness inhibitors or cyst(e)inase has been established many preclinical studies but not reached stage clinical trials patients. A better understanding functions regulating interacting with redox-active proteins their substrates could promising this review intends understand role antioxidant signaling, regulators bioavailability cancer, linking signaling metabolism targeting novel therapeutics.

Language: Английский

Citations

90
Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience DOI
Jaewang Lee, Jong‐Lyel Roh

Cancer Letters, Journal Year: 2023, Volume and Issue: 559, P. 216119 - 216119

Published: March 7, 2023

Language: Английский

Citations

58
miR-509–5p promotes colorectal cancer cell ferroptosis by targeting SLC7A11 DOI
Mahmoud A. Elrebehy, Tamer M. Abdelghany,

Mostafa M. Elshafey

et al.

Pathology - Research and Practice, Journal Year: 2023, Volume and Issue: 247, P. 154557 - 154557

Published: May 20, 2023

Language: Английский

Citations

47
ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability DOI Creative Commons
Qingyu Zhang, Ning Li, Limei Deng

et al.

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 8, 2023

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains survival promotes cancer metastasis in cells. Ferroptosis is a type necrosis caused by an overload oxidation, has been demonstrated to be involved metastasis. However, the mechanism fatty acid metabolism regulates anti-ferroptosis signaling pathways not fully understood. The formation ovarian spheroids helps counteract hostile microenvironment peritoneal cavity with low oxygen, shortage nutrients, subjected platinum therapy. Previously, we that Acyl-CoA synthetase long-chain family member 1 (ACSL1) metastases cancer, but still well elucidated. In this study, demonstrate under exposure chemotherapy increased levels proteins as ACSL1. Inhibition ferroptosis can enhance spheroid vice versa. Genetic manipulation ACSL1 expression showed reduced level oxidation resistance ferroptosis. Mechanistically, N-myristoylation suppressor (FSP1), resulting inhibition its degradation translocation membrane. increase myristoylated FSP1 functionally counteracted oxidative stress-induced Clinical data also suggested protein was positively correlated negatively markers 4-HNE PTGS2. conclusion, study enhances antioxidant capacity increases modulating myristoylation FSP1.

Language: Английский

Citations

44
Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells DOI Creative Commons

Chenfeng Han,

Minmin Ge,

Pengfei Xing

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 15, 2024

Abstract Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer may preferentially rely on certain amino acids for rapid growth and metastasis. the other sufficient nutrient availability uptake are necessary mounting an effective cell anti-tumor response in tumor microenvironment (TME). Here we demonstrate that outcompete cystine due high Slc7a11 expression. This competition induces T-cell exhaustion ferroptosis, characterized by diminished memory formation cytokine secretion, increased PD-1 TIM-3 expression, as well intracellular oxidative stress lipid-peroxide accumulation. Importantly, either deletion or intratumoral supplementation improves immunity. Mechanistically, deprivation disrupts glutathione synthesis, but promotes CD36 mediated lipid dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) synthesis prevents upregulation, thus boosting Our findings reveal metabolic checkpoint orchestrates survival differentiation, highlight Gclc a potential therapeutic target enhancing function.

Language: Английский

Citations

28
Recent Progress in Anti‐Tumor Nanodrugs Based on Tumor Microenvironment Redox Regulation DOI

Lan Yao,

Zhu Xiang,

Yunyi Shan

et al.

Small, Journal Year: 2024, Volume and Issue: 20(25)

Published: Jan. 25, 2024

Abstract The growth state of tumor cells is strictly affected by the specific abnormal redox status microenvironment (TME). Moreover, reactions at biological level are also central and fundamental to essential energy metabolism in tumors. Accordingly, anti‐tumor nanodrugs targeting disruption this homeostasis have become one hot spots field research due effectiveness TME modulation efficiency mediated interference. This review discusses latest results therapy, which regulate levels oxidants or reductants through a variety therapeutic strategies, ultimately breaking original “stable” promoting cell death. With gradual deepening study on vigorous development nanomaterials, it expected that more nano drugs based regulation will be designed even applied clinically.

Language: Английский

Citations

20
Donafenib activates the p53 signaling pathway in hepatocellular carcinoma, induces ferroptosis, and enhances cell apoptosis DOI Creative Commons
Jiaming Liang, Meifeng Chen, Guohong Yan

et al.

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 3, 2025

Donafenib is an improved version of sorafenib in which deuterium substituted into the drug's chemical structure, enhancing its stability and antitumor activity. exhibits enhanced activity better tolerance than preclinical clinical studies. However, specific mechanism effect on hepatocellular carcinoma has not been reported. Iron deposition a cell death pattern caused by disturbances iron metabolism. Apoptosis form programmed death. They may interact with each other during This study mainly explores potential donafenib activating p53 signaling pathway, inducing deposition, apoptosis carcinoma. Hepa1-6 Huh7 cells were treated various concentrations donafenib. Scratch healing pore migration tests conducted. Analyze through flow cytometry TUNEL fluorescence labeling. RNA sequencing was conducted both untreated donafenib-treated cells. The key proteins involved ferroptosis (SLC7A11, GPX4) (caspase3, caspase8, Bax, Bcl-2, p53) then evaluated using immunoblotting immunohistochemical staining. Reactive oxygen species (ROS) levels cancer measured. treatment resulted dose-dependent decrease proliferation, migration, invasion capabilities There increase rates ROS accumulation, reduction tumor volume. underwent significant changes. activates induce ferroptosis, enhance apoptosis, suggesting as effective therapeutic agent for HCC.

Language: Английский

Citations

2
Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis DOI Creative Commons

Xiangying Yan,

Yudong Liu,

Congchong Li

et al.

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: June 6, 2023

Abstract Background Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was evaluate anti-cancer efficacy Pien-Tze-Huang (PZH), and investigate the underlying mechanisms by integrating transcriptional regulatory network analysis experimental validation. Methods A diethylnitrosamine (DEN)-induced HCC model in rats established used PZH. After detecting transcriptomic profiling, “disease-related gene–drug effective target” interaction constructed, candidate targets PZH against malignant were identified verified vitro. Results effectively alleviated pathological changes cirrhosis, inhibited tumor formation growth DEN-induced rats. Additionally, administration reduced levels various function-related serological indicators significantly. Mechanically, ferroptosis-related SLC7A11-GSH-GPX4 axis might one potential HCC. Especially, high SLC7A11 expression associated with poor prognosis patients. Experimentally, markedly increased trivalent iron ferrous ion, suppressed GPX4 proteins, GSH/GSSG ratio liver tissues Conclusions Our data offer an evidence that improve microenvironment prevent occurrence through promoting ferroptosis cells via inhibiting axis, implying drug prevention treatment at early stage.

Language: Английский

Citations

27
Disulfidptosis decoded: a journey through cell death mysteries, regulatory networks, disease paradigms and future directions DOI Creative Commons
Jinyu Chen,

Boyuan Ma,

Yubiao Yang

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: April 29, 2024

Abstract Cell death is an important part of the life cycle, serving as a foundation for both orderly development and maintenance physiological equilibrium within organisms. This process fundamental, it eliminates senescent, impaired, or aberrant cells while also promoting tissue regeneration immunological responses. A novel paradigm programmed cell death, known disulfidptosis, has recently emerged in scientific circle. Disulfidptosis defined accumulation cystine by cancer with high expression solute carrier family 7 member 11 (SLC7A11) during glucose starvation. causes extensive disulfide linkages between F-actins, resulting their contraction subsequent detachment from cellular membrane, triggering death. The RAC1-WRC axis involved this phenomenon. sparked growing interest due to its potential applications variety pathologies, particularly oncology, neurodegenerative disorders, metabolic anomalies. Nonetheless, complexities regulatory pathways remain elusive, precise molecular targets have yet be definitively identified. manuscript aims meticulously dissect historical evolution, underpinnings, frameworks, implications disulfidptosis various disease contexts, illuminating promise groundbreaking therapeutic pathway target.

Language: Английский

Citations

11
Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma DOI Creative Commons
Xiaodong Li,

Fanguang Meng,

Hankang Wang

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Ferroptosis is a type of controlled cell death caused by lipid peroxidation, which results in the rupture membrane. ferroptosis has been repeatedly demonstrated over past ten years to be significant factor number diseases. The liver iron storage organ, thus will have great potential treatment particularly prevalent HCC. In opening section this article, we give general summary pertinent molecular mechanisms, signaling pathways, and associated characteristics ferroptosis. primary regulating mechanisms during are then briefly discussed, conclude summarizing development novel therapeutic strategies used treat HCC recent years. crucial strategy for offers new perspectives on cancer.

Language: Английский

Citations

10