Abstract
Bisdemethoxycurcumin (BDMC), a natural derivative of curcumin with improved solubility and stability, has shown potential cardioprotective properties. This study investigated the efficacy and underlying mechanisms of BDMC in heart failure with preserved ejection fraction (HFpEF) using both in vivo and in vitro models. The HFpEF mouse model was established using a high-fat diet and L-NAME. BDMC treatment improved cardiac function, attenuated myocardial fibrosis, and exhibited antioxidant effects. Mechanistically, integrated network pharmacology and proteomics identified TGFBR1 as a potential target. BDMC inhibited cardiac fibroblast activation by suppressing TGFBR1 expression and SMAD2/3 phosphorylation. Molecular docking and dynamics simulations confirmed stable binding between BDMC and TGFBR1. These findings demonstrate that BDMC mitigates myocardial fibrosis in HFpEF, primarily by competitively inhibiting the binding of TGF-β and TGFBR1, achieving the effect of inhibiting cardiac fibroblast activation.