Kirenol attenuates pressure overload-induced heart failure by enhancing autophagy in macrophages

Heart failure (HF) is characterized by chronic inflammation and pathological remodeling, with macrophage-mediated oxidative stress and inflammasome activation playing key roles in disease progression. Mitophagy regulates mitochondrial quality control and restrains inflammatory activation.

We investigated whether Kirenol, a flavonoid with antioxidant and autophagy-enhancing properties, ameliorates pressure overload-induced HF via mitophagy regulation in macrophages. A murine transverse aortic constriction (TAC) model was employed. Cardiac function, remodeling, and inflammation were assessed by echocardiography, histology, qPCR, immunoblotting, and flow cytometry. In vitro studies were conducted in Ang II-stimulated bone marrow-derived macrophages.

Kirenol significantly improved cardiac function, reduced hypertrophy and fibrosis, and suppressed inflammatory responses in TAC mice. Mechanistically, Kirenol enhanced macrophage mitophagy, reduced mitochondrial ROS production, and inhibited NLRP3 inflammasome activation and IL-1β release. These protective effects were abrogated by mitophagy inhibition using cyclosporin A.

Kirenol exerts cardioprotective effects in pressure overload-induced HF by promoting macrophage mitophagy and suppressing inflammasome-mediated inflammation. This identifies Kirenol as a potential therapeutic agent targeting immune-metabolic dysfunction in HF.