In this study, integrated in vivo (TAC mouse model), in vitro (Ang II-induced HL-1 cardiomyocytes), and network pharmacology experiments confirm that hopeaphenol exerts a protective effect against pressure overload-induced cardiac hypertrophy and delays heart failure progression.Mechanistically, hopeaphenol directly binds to AMPK (validated by molecular docking with two AMPK structures and CETSA) to activate the AMPK/SIRT1 signaling pathway. Here, AGT is linked to heart failure.