PITX2 is a homeodomain transcription factor primarily known for establishing left-right asymmetry during embryonic development 1. In the adult heart, PITX2 is specifically expressed in left atrial cardiomyocytes, where it regulates critical cardiac functions 1. PITX2 controls mitochondrial gene expression and metabolic homeostasis; PITX2 deficiency impairs mitochondrial respiration and shifts metabolism toward glycolysis, causing disorganized sarcomeres and increased spontaneous beating rates 2. Beyond cardiac development, PITX2 is essential for odontogenesis and iris morphogenesis 3. Mechanistically, PITX2 acts as a redox regulator that suppresses mitochondrial ROS production in cardiomyocytes; its expression is suppressed by Nrf3-mediated promoter methylation following cardiac injury 4. PITX2 expression is conversely upregulated by NOX2-derived ROS in obesity-mediated atrial fibrillation 5. Clinically, PITX2 variants are strongly associated with atrial fibrillation risk; genome-wide association studies identified PITX2 on chromosome 4 as a major AF susceptibility locus 6, and reduced PITX2 levels correlate with atrial cardiomyopathy and electrical remodeling 1. PITX2 mutations also cause Axenfeld-Rieger syndrome with ocular anterior segment dysgenesis 7.