In conclusion, we provide evidence that TGFBR1 gene silencing inhibits myocardial fibrosis, myocardial hypertrophy, and myocardial remodeling and improves cardiac function in HFpEF mice, possibly through the modulation of the Smad2/3 fibrosis pathway as well as the TAK1-mediated signaling pathways of PANoptosis and cardiac hypertrophy. Here, SMAD2 is linked to Myocardial fibrosis.