Trilobatin, a Natural Dihydrochalcone, Stabilizes Nrf2 to Protect the Heart from Angiotensin II–Induced Oxidative and Hypertrophic Stress

Aims: Oxidative stress–driven cardiac remodeling is a key pathological feature of heart failure and hypertensive heart disease, yet effective antioxidant therapies remain limited. This study aimed to determine whether the natural dihydrochalcone trilobatin (Tri) protects against angiotensin II (Ang II)–induced cardiac remodeling by alleviating oxidative stress and improving mitochondrial function, and to elucidate its underlying mechanisms. Results: Tri treatment significantly improved Ang II–induced cardiac dysfunction, restoring ejection fraction and fractional shortening, and reduced myocardial hypertrophy, as evidenced by decreased cardiomyocyte cross-sectional area and downregulation of hypertrophic markers, including atrial natriuretic peptide ( ANP ), B-type natriuretic peptide ( BNP ), and beta-myosin heavy chain (β-MHC) . Tri enhanced nuclear factor erythroid 2–related factor 2 (Nrf2) nuclear translocation and upregulated downstream antioxidant genes, restoring redox balance and mitochondrial integrity. In vitro , Tri reduced reactive oxygen species and lipid peroxidation, preserved mitochondrial membrane potential, and improved bioenergetic function. Mechanistically, Tri directly targets Nrf2 and enhances its stability by suppressing ubiquitination, with T447 identified as a key interaction residue whose mutation attenuated Tri-induced Nrf2 signaling. Notably, silencing and inhibition of Nrf2 abolished Tri’s protective effects, establishing Nrf2 as essential for its action. Innovation: This study introduces Tri as a novel Nrf2-stabilizing agent with dual antioxidant and mitochondrial-protective properties, offering a promising therapeutic strategy for oxidative stress–driven cardiovascular diseases. These findings bridge natural product pharmacology with redox biology and highlight a translational path toward heart failure intervention. Conclusion: We identify the dihydrochalcone compound Tri as a potent cardioprotective agent that stabilizes and activates Nrf2 signaling to counteract oxidative and hypertrophic stress. Antioxid. Redox Signal. 00, 000–000.