Pitx2, a member of the bicoid family of homeodomain transcription factors, is crucial in morphogenesis. It is involved in regulating right-left differentiation of the embryonic heart, thorax, and aorta, and also plays a role in skeletal-muscle development as well as satellite-cell differentiation in adult muscle [1,3]. In addition, it functions as a transcription factor for GPX4 in pancreatic cancer cells, protecting them from ferroptosis [5].

In the context of atrial fibrillation, Pitx2 deficiency in murine models leads to electrical and structural remodelling, and impaired heart repair [1]. In human induced pluripotent stem cell-derived atrial cardiomyocytes, PITX2 knockout recapitulates some electrical remodeling findings seen in persistent atrial fibrillation, such as lower force, altered expression of CACNA1C and L-type Ca2+ current density, and changes in action potential characteristics [4]. PITX2-deficient human induced pluripotent stem cell-derived atrial cardiomyocytes also show mitochondrial dysfunction, including an increased number of smaller mitochondria, altered mitochondrial protein expression, and a metabolic shift to glycolysis [2].

In conclusion, Pitx2 is essential for normal development of multiple organs and tissues, including the heart and skeletal muscle. Model-based research, especially gene knockout in mouse models and human induced pluripotent stem cell-derived cardiomyocytes, has revealed its role in atrial fibrillation through its impact on electrical and structural remodelling, as well as mitochondrial function. This understanding may provide new insights for treating atrial fibrillation and other related diseases [1,2,4].