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 9 publications

(5 citation statements)

References 45 publications

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“…A significant accomplishment of this study is the novel application of existing epigenetic drugs for treating meniscus tear injuries. Our selected drug candidates, GSKJ4 (a histone demethylase inhibitor) [31][32][33][34] and C646 (a histone acetyltransferase inhibitor) [35][36][37] effectively restored the migration speed of the inner meniscus cells under TNF-α treatment. This aligns with prior research suggesting that inflammatory cytokines activate JMJD3 via the NF-kB pathway, diminishing…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic Dynamics in Meniscus Cell Migration and its Zonal Dependency in Response to Inflammatory Conditions: Implications for Regeneration Strategies

Zhang,

Wang

et al. 2024

Preprint

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Meniscus injuries pose significant challenges in clinical settings, primarily due to the intrinsic heterogeneity of the tissue and the limited efficacy of current treatments. Endogenous cell migration is crucial for the healing process, yet the regulatory mechanisms of meniscus cell migration and its zonal dependency within the meniscus are not fully understood. Thus, this study investigates the role of epigenetic mechanisms in governing meniscus cell migration under inflammatory conditions, with a focus on their implications for injury healing and regeneration. Here, we discovered that a proinflammatory cytokine, TNF-α treatment significantly impedes the migration speed of inner meniscus cells, while outer meniscus cells are unaffected, underscoring a zonal-dependent response within the meniscus. Our analysis identified distinct histone modification patterns and chromatin dynamics between inner and outer meniscus cells during migration, highlighting the necessity to consider these zonal-dependent properties in devising repair strategies. Specifically, we found that TNF-α differentially influences histone modifications, particularly H3K27me3, between the two cell types. Transcriptome analysis further revealed that TNF-α treatment induces substantial gene expression changes, with inner meniscus cells exhibiting more pronounced alterations than outer cells. Gene cluster analysis pointed to distinct responses in chromatin remodeling, extracellular matrix assembly, and wound healing processes between the zonal cell populations. Moreover, we identified potential therapeutic targets by employing existing epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), to successfully restore the migration speed of inner meniscus cells under inflammatory conditions. This highlights their potential utility in treating meniscus tear injuries. Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insights into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis.

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Section: Discussionmentioning

confidence: 99%

“…Specifically, we employed GSKJ4, an inhibitor of the H3K27me3 demethylase JMJD3, known to elevate the overall level of H3K27me3 in cells [31][32][33][34] , and C646, an inhibitor of the histone acetyltransferase p300, which reduces the overall level of histone acetylation [35][36][37] .…”

Section: Inner Meniscus Cellsmentioning

confidence: 99%

Epigenetic Dynamics in Meniscus Cell Migration and its Zonal Dependency in Response to Inflammatory Conditions: Implications for Regeneration Strategies

Zhang,

Wang

et al. 2024

Preprint

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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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“…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: 99%

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

Cited by 9 publications

References 45 publications

Epigenetic Dynamics in Meniscus Cell Migration and its Zonal Dependency in Response to Inflammatory Conditions: Implications for Regeneration Strategies

Epigenetic Dynamics in Meniscus Cell Migration and its Zonal Dependency in Response to Inflammatory Conditions: Implications for Regeneration Strategies

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

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