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.