更新于：2024-11-01

12/15-LOX x PEBP1

更新于：2024-11-01

基本信息

关联

项与 12/15-LOX x PEBP1 相关的药物

FerroLOXIN-2

靶点

12/15-LOX x PEBP1

作用机制

12/15-LOX抑制剂 [+1]

在研机构

University of Pittsburgh

原研机构

University of Pittsburgh

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

FerroLOXIN-1

靶点

12/15-LOX x PEBP1

作用机制

12/15-LOX抑制剂 [+1]

在研机构

University of Pittsburgh

原研机构

University of Pittsburgh

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 12/15-LOX x PEBP1 相关的临床结果

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100 项与 12/15-LOX x PEBP1 相关的转化医学

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0 项与 12/15-LOX x PEBP1 相关的专利（医药）

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项与 12/15-LOX x PEBP1 相关的文献（医药）

2023-10-01·Aging cell

Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Article

作者: Huang, Rui-Ting ; Gong, Hai-Biao ; Huang, Zi-Han ; Lin, Xiao-Min ; Sun, Jie ; He, Rong-Rong ; Li, Yi-Fang ; Huang, Feng ; Wang, Guan ; Wang, Rong ; Duan, Wen-Jun ; Sun, Wan-Yang ; Pan, Ming-Hai ; Liu, Hai-Zhi ; Kurihara, Hiroshi ; Wang, Meng

Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.

2023-05-01·Ecotoxicology and environmental safety

Ferroptosis participates in dibutyl phthalate-aggravated allergic asthma in ovalbumin-sensitized mice.

Article

作者: Wu, Yang ; Peng, Qi ; Li, Yan ; Yan, Biao ; Chen, Yenan ; Wei, Yaolu ; Zhang, Yuping ; Yang, Xu ; Ma, Ning ; Ma, Ping

Dibutyl phthalate (DBP), used as a plasticizer, is of wide concern as an environmental pollutant since it has certain immunotoxicity. Although there is growing evidence supporting a link between DBP exposure and allergic airway inflammation, there is less information concerned with whether the ferroptosis pathway is involved in DBP-aggravated allergic asthma in ovalbumin (OVA)-sensitized mice. This study aimed to investigate the role and underlying mechanisms of ferroptosis in DBP-exposed allergic asthmatic mice. Balb/c mice were orally exposed to 40 mg/kg^-1 DBP for 28 days, followed by sensitization with OVA and seven consecutive challenges with nebulized OVA. We analyzed airway hyperresponsiveness (AHR), immunoglobulins, inflammation and pulmonary histopathology, to investigate whether DBP exacerbates allergic asthma in OVA-induced mice. We also measured the biomarkers of ferroptosis (Fe²⁺, GPX4, PTGS2), proteins related to the ferroptosis pathway (VEGF, IL-33, HMGB1, SLC7A11, ALOX15, PEBP1), and indices of lipid peroxidation (ROS, Lipid ROS, GSH, MDA, 4-HNE), to explore the role of ferroptosis in DBP+OVA mice. Finally, we used ferrostatin-1 (Fer-1) as an antagonist against the harmful effects of DBP. The results showed that, DBP+OVA mice had a significant increase in AHR, airway wall remodeling and airway inflammation. Further, we showed that DBP aggravated allergic asthma via ferroptosis and lipid peroxidation, and that Fer-1 inhibited ferroptosis and alleviated the pulmonary toxicity of DBP. These results suggest that ferroptosis participates in the exacerbation of allergic asthma resulting from oral exposure to DBP, highlighting a novel pathway for the connection between DBP and allergic asthma.

2021-07-01·Annals of Translational Medicine4区 · 医学

Prognostic and immune implications of a novel ferroptosis-related ten-gene signature in lung adenocarcinoma

4区 · 医学

Article

作者: Li, Feng ; Ma, Chao ; Luo, Huan

BACKGROUNDLung cancer has been the focus of attention for many researchers in recent years due to its leading contribution to cancer-related death worldwide, with lung adenocarcinoma (LUAD) being the most common histological type. Ferroptosis, a novel iron-dependent form of regulated cell death, can be induced by sorafenib. Emerging evidence shows that triggering ferroptosis has potential as a cancer therapy. This work aimed to build a ferroptosis-related gene signature for predicting the outcome of LUAD.METHODSThe TCGA-LUAD dataset was set as the training cohort, and the GSE72094 and GSE68465 datasets were set as the validation cohorts. Sixty-two ferroptosis-related genes were retrieved from the literature. A univariate Cox regression model was constructed for the training cohort to preliminarily screen for potential prognostic ferroptosis-related genes. A gene signature was generated from a LASSO Cox regression model and assessed with the training and validation cohorts through Kaplan-Meier, Cox, and ROC analyses. In addition, the correlation between the risk score and autophagy-related genes was determined by the Pearson test. Finally, GSEA and immune infiltrating analyses were performed to better study the functional annotation of the signature and the role of each kind of immune cell.RESULTSA ten-gene signature was constructed from the training cohort and validated in three cohorts by Kaplan-Meier and Cox regression analyses, revealing its independent prognostic value in LUAD. Moreover, a ROC analysis conducted with all cohort data confirmed the predictive ability of the ten-gene signature for LUAD prognosis. A total of 62.85% (308/490) of autophagy-related genes were found to be significantly correlated with risk scores. GSEA detailed the exact pathways related to the gene signature, and immune-infiltrating analyses identified crucial roles for resting mast cells and resting dendritic cells in the prognosis of LUAD.CONCLUSIONSWe identified a novel ferroptosis-related ten-gene signature (PHKG2, PGD, PEBP1, NCOA4, GLS2, CISD1, ATP5G3, ALOX15, ALOX12B, and ACSL3) that can accurately predict LUAD prognosis and is closely linked to resting mast cells and resting dendritic cells.