GPX4-independent ferroptosis—a new strategy in disease’s therapy

Ma, Tianyu; Du, Jingtong; Zhang, Yufeng; Wang, Yuyao; Wang, Bingxuan; Zhang, Tianhong

doi:10.1038/s41420-022-01212-0

Cited by 83 publications

(33 citation statements)

References 82 publications

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“…Glutathione peroxidases (GPXs) gene belongs to the antioxidant family, which is the main selenoprotein in human body. Compared with other GPXs members, GPX4 directly reduces lipid hydrogen peroxide into non-toxic lipid alcohols in the membrane and acts as the main regulator in the process of ferroptosis 31 . In addition, SLC7A11, encoding cystine/glutamate xCT transporter, is also a key gene involved in regulating ferroptosis 32 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis

Zhao

Wang

Liu

et al. 2023

Sci Rep

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To investigate the effect of pentoxifylline (PTX) on Chlorine (Cl2)-induced acute lung injury (ALI) by single-cell RNA sequencing (scRNA-seq). Female BALB/c mice were exposed to Cl2 at 400 ppm for 15 min. H&E staining was used to observe the degree of lung injury. scRNA-seq was conducted to analysis of normal and Cl2-exposed mice lung tissues. Immunofluorescence was used to observe genes of interest. Thirty-two mice were randomly divided into four groups: Control, Cl2, Cl2+Fer-1, Cl2+PTX. TEM, WB and ELISA were used to detect ferroptosis-related indicators. The 5, 8, 10, 12, 16, 20 clusters were epithelial cells and 4, 15, 18, 19, 21 clusters were endothelial cells. Pseudo-time analysis revealed the differentiation trajectory of epithelial cells and key regulatory genes (Gclc, Bpifa1, Dnah5 and Dnah9) during the process of injury. Cell–cell communication analysis identified several important receptor–ligand complexes (Nrp1-Vegfa, Nrp2-Vegfa, Flt1-Vegfa and Flt4-Vegfa). Ferroptosis were found up-regulated in epithelial and endothelial cells by GSVA analysis. Highly expressed genes to which closely related ferroptosis were found by SCENIC analysis. PTX could significantly decrease the levels of MDA and abnormal high expression of solute carrier family 7 member 11 (SLC7A11, the key transporter of cystine) as well as increase the expression of GSH/GSSG and glutathione peroxidase 4 (GPX4) (p < 0.05). This study revealed novel molecular features of Cl2-induced ALI. PTX may be a potential specific drug by inhibiting the process of ferroptosis in epithelial and endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis

Zhao

Wang

Liu

et al. 2023

Sci Rep

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“…GPX4 is the main regulatory molecule of ferroptosis ( 54 ). It can transform toxic lipid peroxide (ROOH) into non-toxic lipoid (ROH) through GSH so that the fluidity and integrity of the biofilm will not be damaged ( 43 ).…”

Section: Ferroptosismentioning

confidence: 99%

“…It can transform toxic lipid peroxide (ROOH) into non-toxic lipoid (ROH) through GSH so that the fluidity and integrity of the biofilm will not be damaged ( 43 ). Whether inhibiting the expression of GPX4 or its enzyme activity, or inhibiting the synthesis of GSH, it can induce the occurrence of ferroptosis ( 54 , 55 ).…”

Section: Ferroptosismentioning

confidence: 99%

Section: Ferroptosismentioning

confidence: 99%

“…GPX4 is the main regulator of ferroptosis ( 54 ). The inhibition of GPX4 expression by RNAi can induce ferroptosis, while the overexpression of GPX4 can resist the RSL3-induced ferroptosis ( 54 ). RSL3 can covalently bind with selenocysteine at the active site of GPX4 and directly inhibit the enzyme activity of GPX4, thus inducing ferroptosis ( 54 ); as an inhibitor of GPX4, the artificial small molecule compound ML162 can also induce ferroptosis ( 57 ) ( Figure 2 ).…”

Section: Ferroptosismentioning

confidence: 99%

See 2 more Smart Citations

The role of Hippo pathway in ferroptosis

Xiang

Jiang²,

Du³

2023

Front. Oncol.

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The role of Hippo pathway in ferroptosisThe Hippo pathway is mainly composed of mammalian serine/threonine (Ste20)like kinases 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and transcriptional coactivator Yes-associated protein (YAP), and is closely related to cell growth, survival, proliferation, and migration; tissue and organ size control; and tumorigenesis and development. Ferroptosis is a regulated form of cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS) and the depletion of plasma membrane polyunsaturated fatty acids (PUFAs), which is caused by the imbalance of oxidation and the antioxidant system. This article elaborates the role of Hippo pathway in ferroptosis, providing ideas for the regulation of cell fate and the treatment of tumors.

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Engineered Bacteria Manipulate Cysteine Metabolism to Boost Ferroptosis‐Based Pancreatic Ductal Adenocarcinoma Therapy

Qiao,

Wang,

Huang

et al. 2024

Advanced Materials

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Cysteine metabolism is a key determinant of the defense against ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Blocking cysteine metabolism may trigger potent ferroptosis in PDAC cells by generating lipid peroxides during tumor metabolic processes. However, current methods to limit cysteine availability fall short, failing to efficiently block cysteine metabolism due to inadequate tumor targeting and compensatory cysteine sources. Inspired by sulfur‐metabolizing bacteria, synthetic biology to develop an engineered bacterium capable of directly depleting cysteine to block its metabolism is used. Acting as a living drug, these engineered bacteria colonize the tumor and continuously produce engineered cyst(e)inase enzyme (CGL) under the stimulation of tumor hypoxia. The CGL exhausts the substrate cysteine, completely impeding cysteine metabolism. This process dismantles the ferroptosis defense system in PDAC cells, triggers potent ferroptosis, and achieves efficient treatment. The results demonstrate that engineered bacteria designed for cysteine metabolism modulation possess unparalleled advantages in efficacy, persistence, and precision in blocking cysteine metabolism, making them highly suitable for effective ferroptosis treatment of PDAC.

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GPX4-independent ferroptosis—a new strategy in disease’s therapy

Cited by 83 publications

References 82 publications

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis

Single-cell transcriptomes reveal heterogeneity of chlorine-induced mice acute lung injury and the inhibitory effect of pentoxifylline on ferroptosis

The role of Hippo pathway in ferroptosis

Engineered Bacteria Manipulate Cysteine Metabolism to Boost Ferroptosis‐Based Pancreatic Ductal Adenocarcinoma Therapy

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