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Homocysteine induces ferroptosis in cardiomyocytes by disrupting β-catenin/GPX4 pathway
Yanping Lei1, Rui Liu2, Lewu Xu2
1Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan, China.
Insights
Homocysteine damages heart cells by disrupting beta-catenin signaling, leading to reduced GPX4 expression and ferroptosis. Restoring beta-catenin protects against this homocysteine-induced cardiac injury.
Area of Science:
- Cardiology
- Cell Biology
- Biochemistry
Background:
- Homocysteine is known to damage cardiomyocytes, but the precise mechanism remains unclear.
- Ferroptosis, a regulated cell death pathway, plays a significant role in the development and progression of cardiac diseases.
Purpose of the Study:
- To investigate the role of beta-catenin/GPX4 signaling in homocysteine-induced ferroptosis of cardiomyocytes.
- To elucidate the molecular mechanisms by which homocysteine affects cardiac cells.
Main Methods:
- Established a hyperhomocysteinemia mouse model and treated with deferoxamine (DFO) or ferrostatin-1 (Fer-1).
- Assessed protein expression (beta-catenin, GPX4), lipid reactive oxygen species (ROS), iron, glutathione, cell viability, and mitochondrial morphology.
- Utilized chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays to determine the interaction between beta-catenin and the GPX4 promoter.
Main Results:
- Homocysteine inhibited beta-catenin activity and GPX4 expression, promoting ferroptosis in cardiomyocytes both in vitro and in vivo.
- Overexpression of beta-catenin increased GPX4 expression, thereby inhibiting homocysteine-induced ferroptosis.
- GPX4 was identified as a direct target gene of beta-catenin.
Conclusions:
- Homocysteine induces ferroptosis in cardiomyocytes by impairing beta-catenin signaling.
- This disruption leads to the downregulation of GPX4, a key regulator of ferroptosis, contributing to cardiac damage.
Background:
Homocysteine can cause damage to cardiomyocytes, but the exact mechanism underlying that injury is unknown. And, ferroptosis contributes to both the initiation and progression of cardiac diseases. This study aims to focus on homocysteine to investigate the involvement of β-catenin/GPX4 signaling in ferroptosis of cardiomyocytes.
Methods:
In this study, C57BL/6 mice were utilized to establish an experimental model. Hyperhomocysteinemia was induced in the animal model by administering homocysteine at a concentration of 1.8 g/L in the drinking water. Model mice received the treatment of deferoxamine (DFO) and ferrostatin-1 (Fer-1) as therapeutic interventions. Western blot was utilized to detect β-catenin, FTH1, and GPX4. Lipid ROS, Fe2+, and GSH were detected by biochemical assays. In addition, β-catenin and GPX4 expression were assessed by immunostaining techniques. Cell viability was assessed using CCK-8 assay, and mitochondrial damage was examined by transmission electron microscopy. ChIP combining dual luciferase reporter gene assay was performed to analyze the interaction between β-catenin protein with the promoter of GPX4 gene.
Results:
Homocysteine inhibited β-catenin activity and GPX4 expression, and promoted cardiomyocytes ferroptosis in vitro and in vivo. Overexpression of β-catenin promoted the expression of GPX4 and subsequently inhibited homocysteine-induced ferroptosis in cardiomyocytes. Further, results from the ChIP assay and dual-luciferase reporter assay indicated that GPX4 acted as a target gene of β-catenin.
Conclusion:
Homocysteine induces ferroptosis in cardiomyocytes by disrupting β-catenin activity, subsequently downregulating its target gene, GPX4.
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