Using fructose-exposed rat and H9c2 cell models, we provided the evidence that ROS induced Pitx2c-mediated miR-15b low expression and provoked p-p53-dependent TGF-β1/Smads signaling activation, subsequently promoting CTGF-mediated myocardial fibrosis. The gene discussed is TGFB1; the disease is Myocardial fibrosis.