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Inhibition of KDM5A alleviates ferroptosis in myocardial infarction via the GDF15-GPX4 axis
Abstract:
Myocardial infarction (MI) is an acute cardiovascular condition with a poor prognosis, imposing substantial disease and economic burdens worldwide. The histone demethylase KDM5A is known to respond to oxygen levels; however, its role in MI remains unclear. Ferroptosis plays a decisive role in myocardial injury; however, whether it is regulated by KDM5A epigenetically remains unknown. Here, we establish an MI mouse model via left anterior descending coronary artery ligation and a hypoxic HL-1 cardiomyocyte model. Cardiac function, infarct size, and ferroptosis markers (Fe 2 + and MDA) are assessed following KDM5A pharmacological inhibition or genetic manipulation. Epigenetic mechanisms are investigated using Cut&Tag analysis, qPCR, and western blot analysis. The results reveal that KDM5A promotes ferroptosis and aggravates cardiac injury. Inhibition of KDM5A significantly alleviates infarct damage. Cut&Tag analysis indicates that KDM5A binds to the Gdf15 promoter, thereby removing H3K4me3 and suppressing Gdf15 transcription. These changes result in the downregulation of glutathione peroxidase 4 (GPX4) and enhance ferroptosis. These findings suggest that KDM5A drives cardiomyocyte ferroptosis through the GDF15-GPX4 axis. This study identifies KDM5A as an epigenetic regulator of ferroptosis and a promising therapeutic target for MI.
Insights
The histone demethylase KDM5A promotes ferroptosis and worsens heart attacks. Inhibiting KDM5A reduces heart damage by targeting the GDF15-GPX4 pathway, offering a new therapeutic strategy for myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Cell Death Mechanisms
Background:
- Myocardial infarction (MI) is a leading cause of death globally, with limited treatment options.
- The role of histone demethylase KDM5A in MI and its connection to ferroptosis are not well understood.
Purpose of the Study:
- To investigate the role of KDM5A in myocardial infarction and ferroptosis.
- To elucidate the epigenetic mechanisms by which KDM5A influences cardiac injury.
Main Methods:
- Established MI mouse and cardiomyocyte hypoxia models.
- Assessed cardiac function, infarct size, and ferroptosis markers.
- Utilized KDM5A inhibition (pharmacological and genetic) and epigenetic analysis (Cut&Tag, qPCR, Western blot).
Main Results:
- KDM5A inhibition significantly reduced infarct size and improved cardiac function.
- KDM5A epigenetically suppressed Gdf15 expression by removing H3K4me3 at its promoter.
- This led to decreased GPX4 levels, promoting ferroptosis and exacerbating cardiac injury.
Conclusions:
- KDM5A promotes cardiomyocyte ferroptosis and cardiac injury in MI via the GDF15-GPX4 axis.
- KDM5A acts as an epigenetic regulator of ferroptosis.
- Targeting KDM5A presents a potential therapeutic strategy for myocardial infarction.