Modulation of Ferroptosis by the Irx3-Etfa Pathway Protects Against Cardiac Hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Mitochondrial Biology

Background:

• Pathological cardiac hypertrophy contributes significantly to heart failure.
• Ferroptosis and mitochondrial dysfunction are common in cardiac hypertrophy.
• Upstream transcriptional regulation of these processes is poorly understood.

Purpose of the Study:

• To identify transcriptional mechanisms regulating cardiac hypertrophy, ferroptosis, and mitochondrial dysfunction.
• To investigate the role of the Irx3-Etfa axis in pathological cardiac hypertrophy.
• To explore the therapeutic potential of targeting the Irx3-Etfa pathway.

Main Methods:

• Integrative bioinformatics analysis of transverse aortic constriction (TAC)-induced hypertrophic heart datasets.
• Identification of mitochondria-related differentially expressed genes (MitoDEGs).
• Transcription factor prediction and experimental validation using in vivo and in vitro models, including adeno-associated virus-mediated gene manipulation.

Main Results:

• Identified Etfa as a hub MitoDEG directly regulated by transcription factor Irx3, which is upregulated in hypertrophic hearts.
• Demonstrated that the Irx3-Etfa axis suppresses ferroptosis and attenuates hypertrophic remodeling.
• Showed that Irx3 or Etfa overexpression alleviates cardiomyocyte hypertrophy and ferroptotic injury, while Etfa knockdown abolishes Irx3's protective effects.

Conclusions:

• Revealed a novel transcriptional pathway linking mitochondrial metabolism to ferroptosis regulation in cardiac hypertrophy.
• The Irx3-Etfa axis plays a crucial role in mitigating pathological cardiac hypertrophy and ferroptosis.
• The Irx3-Etfa axis represents a promising therapeutic target for treating pathological cardiac hypertrophy and heart failure.