GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Xu, Kai; Liu, Xiang; Wen, Bangchun; Liu, Yazhou; Zhang, Wei; Hu, Xiaolin; Chen, Ling; Hang, Weijian; Chen, Juan

doi:10.3389/fcvm.2022.907747

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…For example, it has been demonstrated that metformin and GSK-J4 may ameliorate lipotoxicity to cardiomyocytes via ferroptosis. 23 , 29 Quercetin, which decreases the expression of ATF3, could alleviate acute kidney injury via inhibition of ferroptosis. 30 Overall, ferroptosis might play an important role in PA-treated endothelial dysfunction and cell death.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis highlights the role of ferroptosis in palmitic acid–induced endothelial dysfunction

Tan

Nan

et al. 2023

Sexual Medicine

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Background Palmitic acid (PA) has a lipotoxic effect on blood vessels, leading to endothelial dysfunction and cell death. The underlying mechanisms are not yet fully understood. Aim We sought to investigate the effects of PA on endothelial cells, with an emphasis on ferroptosis. Methods Rat corpus cavernosum endothelial cells (RCCECs) and human umbilical vein endothelial cells (HUVECs) were treated with PA to induce a pattern of cell death, as evidenced by the evaluation of cell viability. The differentially expressed genes were measured via RNA sequencing to reveal potential mechanisms. The intracellular levels of glutathione (GSH), malondialdehyde (MDA), ferrous ion (Fe2+), and reactive oxygen species (ROS) were evaluated using commercial kits. Western blot was performed to determine the expressions of relative proteins. Outcomes At the end of the study period, the evaluated outcomes were cell viability, transcriptome profiles, the expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), as well as levels of GSH, MDA, Fe2+, and ROS. Results PA-induced cell death of RCCECs and HUVECs was demonstrated in a dose- and time-dependent manner. Based on the findings of RNA-sequencing (RNA-seq), enrichment of many biological processes associated with cell cycle and response to stimulus occurred. More importantly, ferroptosis was highlighted in the bioinformatic analysis of both endothelial cells. The levels of intracellular Fe2+, MDA, and ROS were significantly increased following PA exposure while GSH was decreased, suggesting excessive iron accumulation, development of lipid peroxidation, and imbalanced redox homeostasis. Mechanistically, PA decreased the protein expression levels of GPX4 and SLC7A11 in endothelial cells, both of which played crucial roles in ferroptotic cell death. Clinical Translation This study suggests that ferroptosis may be a useful target for novel therapeutic interventions for endothelial dysfunction and cell death in vascular diseases such as erectile dysfunction. Strengths and Limitations In this study, we found that ferroptosis could participate in PA-induced endothelial dysfunction and cell death. A limitation of the study is that it did not shed light on the overall mechanisms of this process. Therefore, further research on the intricate networks of regulating ferroptosis is needed. Conclusion Overall, the occurrence of ferroptosis was demonstrated in the PA-treated HUVECs and RCCECs in this study.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis highlights the role of ferroptosis in palmitic acid–induced endothelial dysfunction

Tan

Nan

et al. 2023

Sexual Medicine

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“…In contrast, Yu et al demonstrated that EZH2 mitigated the ferroptosis of tongue squamous cell carcinoma cells by suppressing miR-125b-5p but upregulating SLC7A11 expression [203]. Additionally, GSK-J4, a dual inhibitor of histone lysine demethylase 6A/6B that prevents H3K27 demethylation, can suppress palmitic acid (PA)-induced hypersensitivity to ferroptosis by inhibiting ACSL4 expression and lipid peroxidation in cardiomyocytes [204]. KMT2B activated the transcription of riboflavin kinase (RFK) by enhancing the trimethylation of H3K4, which subsequently accelerated tumor necrosis factor-α (TNF-α)/NADPH oxidase 2 (NOX2) axis activation to promote ferroptosis during myocardial ischemia/reperfusion injury [205].…”

Section: Protein Methylation In Ferroptosismentioning

confidence: 98%

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

Wang¹,

Kong²,

Feng³

et al. 2023

Int. J. Biol. Sci.

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Ferroptosis is a form of programmed cell death characterized by elevated intracellular ferrous ion levels and increased lipid peroxidation. Since its discovery and characterization in 2012, considerable progress has been made in understanding the regulatory mechanisms and pathophysiological functions of ferroptosis. Recent findings suggest that numerous organ injuries (e.g., ischemia/reperfusion injury) and degenerative pathologies (e.g., aortic dissection and neurodegenerative disease) are driven by ferroptosis. Conversely, insufficient ferroptosis has been linked to tumorigenesis. Furthermore, a recent study revealed the effect of ferroptosis on hematopoietic stem cells under physiological conditions. The regulatory mechanisms of ferroptosis identified to date include mainly iron metabolism, such as iron transport and ferritinophagy, and redox systems, such as glutathione peroxidase 4 (GPX4)-glutathione (GSH), ferroptosis-suppressor-protein 1 (FSP1)-CoQ10, FSP1-vitamin K (VK), dihydroorotate dehydrogenase (DHODH)-CoQ, and GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4). Recently, an increasing number of studies have demonstrated the important regulatory role played by epigenetic mechanisms, especially DNA, RNA, and protein methylation, in ferroptosis. In this review, we provide a critical analysis of the molecular mechanisms and regulatory networks of ferroptosis identified to date, with a focus on the regulatory role of DNA, RNA, and protein methylation. Furthermore, we discuss some debated findings and unanswered questions that should be the foci of future research in this field.

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“…In tumor cells, the methylation pathway of ACSL4 is generally inhibited, leading to PTM changes or overexpression that promotes tumor cell proliferation. However, the methylation-dependent reduction in ACSL4 levels can also prevent oxidative damage in cardiac myocytes and inhibit cardiomyocyte ferroptosis [ 68 ]. Methylation-dependent inhibition of ACSL4 also has a dual role.…”

Section: Modulation Of Acsl4mentioning

confidence: 99%

The ACSL4 Network Regulates Cell Death and Autophagy in Diseases

Chen

Kang

Liu

et al. 2023

Biology

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Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.

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GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Cited by 7 publications

References 45 publications

Transcriptome analysis highlights the role of ferroptosis in palmitic acid–induced endothelial dysfunction

Transcriptome analysis highlights the role of ferroptosis in palmitic acid–induced endothelial dysfunction

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

The ACSL4 Network Regulates Cell Death and Autophagy in Diseases

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