METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis

Zhuang, Shaowei; Ma, Yan; Zeng, Yuxiao; Lu, Cheng Wei; Yang, Fenghua; Jiang, Nianxin; Ge, Junwei; Ju, Haining; Zhong, Chun-lin; Wang, Jiayi; Zhang, Jiehan; Jiang, Shengyang

doi:10.1007/s10565-021-09660-7

Cited by 77 publications

(66 citation statements)

References 52 publications

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“…The remote cause of this mechanism is usually due to the decline of glutathione synthesis and metabolism-related functions in cells, resulting in the excess of reactive oxygen species [ 11 ]. Many genes such as TFRC, P53, and GPX4 have been proved to be involved in the occurrence and development of ferroptosis [ 12 – 15 ]. As a mechanism related to intracellular metabolism, it has attracted extensive attention in a variety of immune diseases, malignant tumors, and osteoporosis [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Association between Glutathione Metabolism and Ferroptosis in Osteoblasts with Disuse Osteoporosis and the Key Genes Connecting them

Wang

Jia

et al. 2022

Computational and Mathematical Methods in Medicine

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Disused osteoporosis is a kind of osteoporosis, a common age-related disease. Neurological disorders are major risk factors for osteoporosis. Though there are many studies on disuse osteoporosis, the genetic mechanisms for the association between glutathione metabolism and ferroptosis in osteoblasts with disuse osteoporosis are still unclear. The purpose of this study is to explore the key genes and other related mechanism of ferroptosis and glutathione metabolism in osteoblast differentiation and disuse osteoporosis. By weighted gene coexpression network analysis (WGCNA), the process of osteoblast differentiation-related genes was studied in GSE30393. And the related functional pathways were found through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. By combining GSE1367 and GSE100933 together, key genes which were separately bound up with glutathione metabolism and ferroptosis were located. The correlation of these key genes was analyzed by the Pearson correlation coefficient. GSTM1 targeted agonist glutathione (GSH) selected by connectivity map (CMap) analysis was used to interfere with the molding disused osteoporosis process in MC3T3-E1 cells. RT-PCR and intracellular reactive oxygen species (ROS) were performed. Two important pathways, glutathione metabolism and ferroptosis pathways, were found. GSTM1 and TFRC were thought as key genes in disuse osteoporosis osteoblasts with the two mechanisms. The two genes have a strong negative correlation. Our experiment results showed that the expression of TFRC was consistent with the negative correlation with the activation process of GSTM1. The strong relationship between the two genes was proved. Glutathione metabolism and ferroptosis are important in the normal differentiation of osteoblasts and the process of disuse osteoporosis. GSTM1 and TFRC were the key genes. The two genes interact with each other, which can be seen as a bridge between the two pathways. The two genes participate in the process of reducing ROS in disuse osteoporosis osteoblasts.

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Section: Introductionmentioning

confidence: 99%

Exploring the Association between Glutathione Metabolism and Ferroptosis in Osteoblasts with Disuse Osteoporosis and the Key Genes Connecting them

Wang

Jia

et al. 2022

Computational and Mathematical Methods in Medicine

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“…Ferroptosis is a newly discovered type of programmed cell death that involves iron-dependent lipid peroxidation along with the loss of glutathione peroxidase 4 and dense mitochondrial membrane ( Dixon and Stockwell, 2014 ). m 6 A modification, as a new form of post-transcriptional regulatory mechanism, is known to play an important role in ferroptosis ( Shen et al, 2021 ; Zhuang et al, 2021 ). During the ferroptosis of liver fibrosis, the expression of METTL4 was shown to up-regulated; in addition, the level of m 6 A was shown to increase and was enhanced by ferroptosis inducers ( Shen et al, 2021 ).…”

Section: The Role Of M 6 a In Pcdmentioning

confidence: 99%

“…During the ferroptosis of liver fibrosis, the expression of METTL4 was shown to up-regulated; in addition, the level of m 6 A was shown to increase and was enhanced by ferroptosis inducers ( Shen et al, 2021 ). Previous researchers investigated the mechanisms underlying the effect of doxorubicin on cardiotoxicity and found that doxorubicin induced the up-regulation of METTL14 expression and catalyzed the m 6 A modification of RNA KCNQ1OT1 to participate in the ferroptosis of cardio myocytes ( Zhuang et al, 2021 ). Moreover, METTL3 acts as the target of miR-4443, and regulates the expression of FSP1 to mediate the ferroptosis of non-small cell lung cancer ( Song et al, 2021 ).…”

Section: The Role Of M 6 a In Pcdmentioning

confidence: 99%

m6A: An Emerging Role in Programmed Cell Death

Tang

Chen

et al. 2022

Front. Cell Dev. Biol.

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Programmed cell death is an active extinction process, including autophagy, ferroptosis, pyroptosis, apoptosis, and necroptosis. m6A is a reversible RNA modification which undergoes methylation under the action of methylases (writers), and is demethylated under the action of demethylases (erasers). The RNA base site at which m6A is modified is recognized by specialized enzymes (readers) which regulate downstream RNA translation, decay, and stability. m6A affects many aspects of mRNA metabolism, and also plays an important role in promoting the maturation of miRNA, the translation and degradation of circRNA, and the stability of lncRNA. The regulatory factors including writers, erasers and readers promote or inhibit programmed cell death via up-regulating or down-regulating downstream targets in a m6A-dependent manner to participate in the process of disease. In this review, we summarize the functions of m6A with particular reference to its role in programmed cell death.

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“…Proteins associated with iron transport are considered significant indicators of cellular iron homeostasis and are mainly involved in cellular iron uptake (TfR1) and storage (ferritin). As for TfR1, most studies believe that DOX could elevate its expression ( 87 – 89 ). A study believed that TfR1 is critical for the DOX-induced increase in iron uptake.…”

Section: Ferroptosis and Anthracycline-induced Cardiotoxicitymentioning

confidence: 99%

“…After incubation with the specific anti-TfR antibody (12 μg/ml), DOX-induced increase of 55 Fe uptake in bovine aortic endothelial (BAEC) cells was reversed ( 88 ). The mechanism of increased TfR1 could be because DOX inhibited the expression of miR-7-5p by increasing the METTL14-mediated expression of KCNQ1OT1m6A, thus reducing the degradation of TfR1 ( 89 ). In AC16 cells, METTL14 knockdown, KCNQ1OT1 silencing, and miR-7-5p mimic attenuated the DOX-induced increase of Fe 2+ and lipid ROS, and reduced DOX-induced decrease in mtDNA and MMP levels.…”

Section: Ferroptosis and Anthracycline-induced Cardiotoxicitymentioning

confidence: 99%

Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

Yuan

Zhang

et al. 2022

Front. Cardiovasc. Med.

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Anthracyclines (ANTs) are a class of anticancer drugs widely used in oncology. However, the clinical application of ANTs is limited by their cardiotoxicity. The mechanisms underlying ANTs-induced cardiotoxicity (AIC) are complicated and involve oxidative stress, inflammation, topoisomerase 2β inhibition, pyroptosis, immunometabolism, autophagy, apoptosis, ferroptosis, etc. Ferroptosis is a new form of regulated cell death (RCD) proposed in 2012, characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. An increasing number of studies have found that ferroptosis plays a vital role in the development of AIC. Therefore, we aimed to elaborate on ferroptosis in AIC, especially by doxorubicin (DOX). We first summarize the mechanisms of ferroptosis in terms of oxidation and anti-oxidation systems. Then, we discuss the mechanisms related to ferroptosis caused by DOX, particularly from the perspective of iron metabolism of cardiomyocytes. We also present our research on the prevention and treatment of AIC based on ferroptosis. Finally, we enumerate our views on the development of drugs targeting ferroptosis in this emerging field.

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METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis

Cited by 77 publications

References 52 publications

Exploring the Association between Glutathione Metabolism and Ferroptosis in Osteoblasts with Disuse Osteoporosis and the Key Genes Connecting them

Exploring the Association between Glutathione Metabolism and Ferroptosis in Osteoblasts with Disuse Osteoporosis and the Key Genes Connecting them

m6A: An Emerging Role in Programmed Cell Death

Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

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