Honokiol Inhibits Arsenic Trioxide–Induced Cardiomyopathy by Modulating Ferroptosis via SIRT3 Signaling Pathway

Abstract Background Our previous studies have confirmed that Honokiol exerts protective effect on cardiomyocytes and cardiac tissue against ATO-induced cardiotoxicity, which is attributed to inhibiting cardiomyocyte apoptosis via reduced oxidative stress.Objectives This research aimed to explore the entire mechanism by which Honokiol provides protection against arsenic trioxide-induced cardiotoxicity.Materials and methods 129S1/SvImJ male wild type (WT) mice and SIRT3-knockout (SIRT3−/−) mice with 129S1 background were applied to verify the pathway of Honokiol on myocardial toxicity of arsenic trioxide; MitoSox, carboxy-DCFDA and Amplex Red were used to detect oxidative stress; ferroptosis-associated markers (MDA, GSH, tissue iron, GPX4 and 4-HNE expression) were tested by test kit or immunohistochemistry; autophagic flux was analyzed by western blot.Results SIRT3 knockout abolishes protective effects of HKL in ATO-induced myocardial injury and hypertrophy; Honokiol protects myocardium from ATO-induced oxidative stress through SIRT3/SOD2 pathway; Honokiol inhibited ATO-induced ferroptosis via the SIRT3 pathway in myocardial tissues; Honokiol improve autophagic flux in cardiomyocytes exposed to ATO treatment. Autophagic flux plays a critical role in protective effect of Honokiol on ATO-induced ferroptosis. The present study confirmed that Honokiol inhibits oxidative stress injury and ferroptosis in cardiomyocytes by promoting the autophagic flux in cardiomyocytes through the activation of SIRT3.