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Updated: Jul 25, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with
Jie Ju1,2, Xin-Min Li2, Xue-Mei Zhao3
1Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China.
Background:
Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function.
Methods:
We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA.
Results:
Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis.
Conclusions:
Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.
Insights
This study identifies a novel circular RNA, FEACR, that protects heart cells from ferroptosis after ischemia and reperfusion injury. FEACR regulates a key signaling pathway, offering potential therapeutic targets for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Cell Death Mechanisms
Background:
- Circular RNAs (circRNAs) are implicated in cardiac cell death following myocardial ischemia and reperfusion (I/R).
- Ferroptosis, a distinct form of cell death, plays a role in myocardial I/R.
- Understanding circRNA regulation in cardiac ferroptosis is crucial for I/R injury.
Purpose of the Study:
- To identify key circRNAs regulating cardiac ferroptosis after myocardial I/R.
- To elucidate the functional mechanisms of identified circRNAs in cardiomyocyte ferroptosis.
- To explore potential therapeutic targets for ferroptosis-related myocardial injury.
Main Methods:
- CircRNA sequencing to identify differentially expressed circRNAs post-I/R.
- Quantitative PCR for circRNA expression analysis and subcellular localization.
- Gain- and loss-of-function experiments to assess circRNA roles in ferroptosis and cardiac damage.
- RNA pull-down assays to identify interacting proteins.
Main Results:
- A ferroptosis-associated circRNA (FEACR) was identified with a regulatory role in cardiomyocyte ferroptosis.
- FEACR overexpression reduced myocardial infarction and improved cardiac function post-I/R.
- FEACR directly bound to NAMPT, stabilizing it and increasing Sirt1 expression, which enhanced FOXO1 activity.
- This cascade upregulated FTH1, a ferroptosis suppressor, thereby inhibiting cardiomyocyte ferroptosis.
Conclusions:
- The circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 axis regulates cardiomyocyte ferroptosis.
- FEACR protects heart function against I/R injury by inhibiting ferroptosis.
- FEACR and its downstream targets represent potential therapeutic strategies for ischemic heart diseases.
