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lnc-MRGPRF-6:1 Promotes ox-LDL-Induced Macrophage Ferroptosis via Suppressing GPX4
Zhihuan You1, Xiaotian Ye1, Meihua Jiang2
1Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China.
Background:
Ferroptosis, a newly discovered mode of cell death, emerges as a new target for atherosclerosis (AS). Long noncoding RNAs (lncRNAs) are involved in the regulation of ferroptosis. In our previous study, lnc-MRGPRF-6:1 was highly expressed in patients with coronary atherosclerotic disease (CAD) and closely associated with macrophage-mediated inflammation in AS. In the present study, we aim to investigate the role of lnc-MRGPRF-6:1 in oxidized-low-density lipoprotein (ox-LDL)-induced macrophage ferroptosis in AS.
Methods:
Firstly, ox-LDL-treated macrophages were used to simulate macrophage injury in AS. Then, ferroptosis-related biomarkers and mitochondrial morphology were detected and observed in ox-LDL-treated macrophages. Subsequently, we constructed lnc-MRGPRF-6:1 knockdown and overexpression of THP-1-derived macrophages and investigated the role of lnc-MRGPRF-6:1 in ox-LDL-induced ferroptosis. Then human monocytes were isolated successfully and were used to explore the role of lnc-MRGPRF-6:1 in macrophage ferroptosis. Likely, we constructed lnc-MRGPRF-6:1 knockdown and overexpression of human monocyte-derived macrophages and detected the expression levels of ferroptosis-related biomarkers. Then, transcriptome sequencing, literature searching, and following quantitative real-time polymerase chain reaction and western blot were implemented to explore specific signaling pathway in the process. It was demonstrated that lnc-MRGPRF-6:1 may regulate ox-LDL-induced macrophage ferroptosis through glutathione peroxidase 4 (GPX4). Eventually, the correlation between lnc-MRGPRF-6:1 and GPX4 was measured in monocyte-derived macrophages of CAD patients and controls.
Results:
The ox-LDL-induced injury in macrophages was involved in ferroptosis. The knockdown of lnc-MRGPRF-6:1 could alleviate ox-LDL-induced ferroptosis in macrophages. Meanwhile, the overexpression of lnc-MRGPRF-6:1 could intensify ox-LDL-induced ferroptosis. Furthermore, the knockdown of lnc-MRGPRF-6:1 could alleviate the decrease of GPX4 induced by RAS-selective lethal compounds 3 (RSL-3). These indicated that lnc-MRGPRF-6:1 may suppress GPX4 to induce macrophage ferroptosis. Eventually, lnc-MRGPRF-6:1 was highly expressed in the monocyte-derived macrophages of CAD patients and was negatively correlated with the expression of GPX4.
Conclusion:
lnc-MRGPRF-6:1 can promote ox-LDL-induced macrophage ferroptosis through inhibiting GPX4.
Insights
Long noncoding RNA MRGPRF-6:1 promotes ferroptosis in macrophages, a key process in atherosclerosis. This study shows lnc-MRGPRF-6:1 inhibits GPX4, worsening oxidized-LDL-induced cell death in coronary artery disease.
Area of Science:
- Molecular Biology
- Cell Death Mechanisms
- Cardiovascular Research
Background:
- Ferroptosis, a distinct cell death pathway, is a potential therapeutic target for atherosclerosis (AS).
- Long noncoding RNAs (lncRNAs) play roles in ferroptosis regulation.
- lnc-MRGPRF-6:1 is upregulated in coronary artery disease (CAD) and linked to macrophage inflammation in AS.
Purpose of the Study:
- To investigate the role of lnc-MRGPRF-6:1 in oxidized-low-density lipoprotein (ox-LDL)-induced macrophage ferroptosis in AS.
- To elucidate the molecular mechanism by which lnc-MRGPRF-6:1 influences macrophage ferroptosis.
Main Methods:
- Macrophages were treated with ox-LDL to induce injury and ferroptosis.
- lnc-MRGPRF-6:1 knockdown and overexpression were performed in THP-1 derived macrophages and human monocyte-derived macrophages.
- Ferroptosis biomarkers, mitochondrial morphology, and the expression of glutathione peroxidase 4 (GPX4) were analyzed.
- Transcriptome sequencing, qRT-PCR, and Western blot were used to identify the signaling pathway.
Main Results:
- Ox-LDL induced ferroptosis in macrophages, evidenced by biomarker changes and altered mitochondrial morphology.
- lnc-MRGPRF-6:1 knockdown alleviated ox-LDL-induced ferroptosis, while its overexpression intensified it.
- lnc-MRGPRF-6:1 was found to suppress GPX4 expression, thereby promoting ferroptosis.
- lnc-MRGPRF-6:1 was highly expressed in monocyte-derived macrophages from CAD patients and negatively correlated with GPX4 levels.
Conclusions:
- lnc-MRGPRF-6:1 promotes ox-LDL-induced macrophage ferroptosis.
- The mechanism involves the inhibition of GPX4 by lnc-MRGPRF-6:1.
- lnc-MRGPRF-6:1 represents a potential therapeutic target for atherosclerosis.
