n-Butylphthalide alleviates obesity-induced cardiomyopathy by binding directly to Keap1.

Abstract

OBJECTIVES: The incidence of cardiovascular disease (CVD) increases with obesity and hyperlipidemia due to elevated oxidative stress (OS). n-Butylphthalide (NBP), an antioxidant derived from celery, has shown promise for treating obesity-induced cardiomyopathy, although its specific target remains unclear. This study explores the mechanism of action of NBP in obesity-induced myocardial injury. METHODS: A high-fat diet (HFD) animal model and an H9C2 myoblast cell model exposed to palmitic acid (PA) were used to measure therapeutic effects of NBP on inflammation, apoptosis, fibrosis, and oxidative stress. RESULTS: NBP alleviated obesity-induced cardiomyopathy by binding to Kelch-like ECH-associated protein-1 (Keap1) at Tyr334, thereby preventing Keap1 from forming a complex with the nuclear factor erythroid 2-related factor 2 (Nrf2). CONCLUSION: This study demonstrates that the antioxidant activity of NBP is mediated through the Nrf2 pathway by blocking the interaction between Keap1 and Nrf2. Additionally, we identify a novel druggable pocket in the Keap1/Nrf2 interaction interface for treating obesity-induced cardiomyopathy.