Chelerythrine triggers the prolongation of QT interval and induces cardiotoxicity by promoting the degradation of hERG channels

Cardiotoxicity is a serious adverse reaction during drug treatment. The cardiac human ether-a-go-go-related gene (hERG) channels play a crucial role in driving cardiac action potential repolarization and are a key target for drug-induced cardiac toxicity. Chelerythrine (CHE) has anticancer effects on various human cancer cells. But little is known about its drug safety currently. The purpose of this study is to explore the key mechanism of cardiac toxicity induced by CHE under pathological conditions. CHE and hypoxia prolonged QT interval and action potential duration compared with control group in guinea pigs, as measured by BL-420S biological acquisition and processing system in conjunction with optical mapping technology. hERG current was measured by patch-clamp technique, and the interaction between ubiquitin molecules and hERG channels was assessed using immunoprecipitation method at the molecular level. The colocalization of proteins and the function of lysosomes were determined via confocal laser scanning microscopy. Further research indicates that CHE enhances the ubiquitination process of hERG proteins by catalyzing the formation of K63 ubiquitin chains, the ubiquitination modification disrupts hERG channel homeostasis, and promotes the degradation of the channel. Mechanistically, CHE accelerates the degradation of hERG channels through lysosomes via HDAC6, which may easily induce cardiotoxicity caused by prolonged QT interval under hypoxic conditions.