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NR1D2 Knockdown Alleviates Myocardial Infarction through Nrf2 Signaling Pathway Activation
Ting Wang1, Helong Xiao2, Meijian Yang3
1Department of Cardiology, Hebei Medical University Third Hospital, No. 139, Ziqiang Road, Shijiazhuang, Hebei, China.
Purpose:
Ferroptosis contributes to myocardial infarction (MI) pathogenesis. However, the role of nuclear receptor subfamily 1 group D member 2 (NR1D2) in MI-associated ferroptosis and its potential interaction with nuclear factor erythroid 2-related factor 2 (Nrf2) pathway remains unclear. We sought to determine whether NR1D2 regulates ferroptosis in MI through the Nrf2 pathway and to evaluate the therapeutic potential of NR1D2 knockdown.
Methods:
Bioinformatic analyses of GEO datasets identified NR1D2 as a key ferroptosis-related gene in MI. In vitro, NR1D2 expression was silenced in HL-1 cardiomyocytes subjected to hypoxia/reoxygenation (H/R) injury. Nrf2 inhibitor ML385 was used to verify pathway involvement. A mouse model of MI was established, and cardiac function was assessed following NR1D2 knockdown with or without ML385 co-treatment.
Results:
NR1D2 expression was significantly upregulated in MI. Its knockdown in H/R-injured cardiomyocytes reduced cell death, inflammation, and ferroptosis, as indicated by decreased Fe²⁺ and malondialdehyde levels and elevated GSH/GSSG ratio. These protective effects were abolished by ML385, confirming Nrf2 dependence. Mechanistically, NR1D2 knockdown activated the Nrf2/HO-1 signaling axis, leading to the upregulation of downstream effectors glutathione peroxidase 4and SLC7A11. In MI mice, NR1D2 knockdown improved cardiac function (increased EF and FS), decreased infarct size, and inhibited ferroptosis-effects that were also negated by ML385.
Conclusion:
NR1D2 aggravates MI injury by suppressing the Nrf2 pathway and promoting ferroptosis. Targeting NR1D2 activates Nrf2 signaling and alleviates ferroptotic damage, revealing a novel regulatory mechanism and identifying NR1D2 as a promising therapeutic target for MI.
Insights
Nuclear receptor subfamily 1 group D member 2 (NR1D2) worsens myocardial infarction (MI) by promoting ferroptosis. Targeting NR1D2 activates the protective nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, offering a novel therapeutic strategy for MI.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Molecular Medicine
Background:
- Ferroptosis, a regulated form of cell death, plays a significant role in the pathogenesis of myocardial infarction (MI).
- The specific role of nuclear receptor subfamily 1 group D member 2 (NR1D2) in MI-associated ferroptosis and its interaction with the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway remain largely unexplored.
Purpose of the Study:
- To investigate whether NR1D2 regulates ferroptosis in myocardial infarction (MI) via the Nrf2 pathway.
- To evaluate the potential therapeutic efficacy of NR1D2 knockdown in mitigating MI-induced ferroptosis and cardiac dysfunction.
Main Methods:
- Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets identified NR1D2 as a key ferroptosis-related gene in MI.
- In vitro studies involved NR1D2 silencing in hypoxia/reoxygenation (H/R)-injured HL-1 cardiomyocytes, with Nrf2 pathway involvement confirmed using the inhibitor ML385.
- A mouse model of MI was established to assess cardiac function following NR1D2 knockdown, with and without ML385 co-treatment.
Main Results:
- NR1D2 expression was significantly upregulated in MI. Knockdown of NR1D2 in H/R-injured cardiomyocytes reduced cell death, inflammation, and ferroptosis markers (Fe²⁺, MDA, GSH/GSSG ratio).
- These protective effects were abrogated by ML385, confirming Nrf2 pathway dependence. NR1D2 knockdown activated the Nrf2/HO-1 signaling axis, upregulating downstream effectors like GPX4 and SLC7A11.
- In vivo, NR1D2 knockdown in MI mice improved cardiac function (EF, FS), reduced infarct size, and inhibited ferroptosis, effects negated by ML385.
Conclusions:
- NR1D2 exacerbates MI injury by suppressing the Nrf2 pathway and promoting ferroptosis.
- Targeting NR1D2 activates Nrf2 signaling, alleviating ferroptotic damage in MI.
- NR1D2 represents a novel therapeutic target for myocardial infarction, offering a new strategy to combat ferroptosis-induced cardiac injury.
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