Inhibition of TAK1/TAB2 complex formation by costunolide attenuates obesity cardiomyopathy via the NF-κB signaling pathway

Background: Chronic and persistent obesity can lead to various complications, including obesity cardiomyopathy. Inhibition of the inflammatory response is an effective measure for the intervention of obesity cardiomyopathy. Numerous studies indicate that costunolide (Cos) can reduce inflammation. However, the role of Cos in obesity cardiomyopathy and its molecular targets remains unknown. Hypothesis/Purpose: We aimed to clarify potential cardioprotective effects and mechanism of Cos against obesity cardiomyopathy. Methods: The model of obesity cardiomyopathy was established by feeding mice with a high-fat diet for 24 weeks. Cos at 10 and 20 mg/kg or vehicle (1% CMC-Na solution) was administered once every two days via oral gavage from the 17th to 24th week. Body weight, heart weight/tibia length, cardiac function, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers, inflammatory factors were assessed. The targets of Cos were predicted through molecular docking. Pull-down assay and biolayer interferometry were used to confirm the target of Cos. Results: Cos effectively reduces obesity-induced cardiomyocyte inflammation, cardiac hypertrophy and fibrosis, thereby improving cardiac function. We confirmed that Cos can interact with TAK1 and inhibit downstream NF-kappa B pathway activation by blocking the formation of the TAK1/TAB2 complex, thus inhibiting inflammatory cytokine release in cardiomyocytes. Conclusion: Our results demonstrated that Cos significantly improved myocardial remodeling and cardiac dysfunction against obesity cardiomyopathy by reducing myocardial inflammation. Therefore, Cos may serve as a promising therapeutic agent in obesity cardiomyopathy.