Tectorigenin alleviates HFpEF by targeting the EGFR-EGR2-Acot1 axis to improve myocardial lipid metabolism.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all heart failure cases worldwide, yet effective targeted therapies remain limited. Tectorigenin (Tec), a bioactive isoflavone derived from traditional Chinese medicine, exhibits diverse cardioprotective effects; however, its therapeutic potential and underlying mechanisms in HFpEF remain incompletely understood. This study aimed to investigate the effects of Tec on HFpEF and elucidate the underlying molecular mechanisms. A mouse model of HFpEF was established using the "two-hit" approach (high-fat diet + L-NAME). In vivo experiments included echocardiography, histological staining, treadmill testing, metabolic assessments, and molecular analyses. In vitro, neonatal rat ventricular myocytes (NRVMs) exposed to palmitic acid (PA) were used to model cardiomyocyte lipotoxicity. RNA sequencing, network pharmacology, molecular docking, surface plasmon resonance, pull-down assays, chromatin immunoprecipitation, and gene silencing were employed to elucidate the regulatory mechanisms. Tec attenuated HFpEF progression and retained therapeutic efficacy when administered after HFpEF establishment. In vitro, Tec alleviated PA-induced cardiomyocyte lipotoxicity. Mechanistically, Tec directly bound EGFR at the E762/M793 sites and inhibited its aberrant activation. Inhibition of EGFR signaling suppressed the downstream EGFR-EGR2 axis, thereby upregulating Acot1 and improving myocardial lipid metabolic homeostasis. Cardiac-specific Acot1 knockdown or pharmacological activation of EGFR markedly attenuated Tec-mediated improvements in cardiac function, remodeling, and myocardial lipid metabolism. Tec ameliorates HFpEF through the EGFR-EGR2-Acot1 axis, highlighting a potential therapeutic strategy for HFpEF.