A new mechanism of therapeutic effect of stachydrine on heart failure by inhibiting myocardial ferroptosis.

Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation and excessive production of ROS. Its morphology is characterized by mitochondrial atrophy, increased mitochondrial membrane density, mitochondrial cristae degeneration and rupture, and unchanged nuclear morphology. Here, we investigated whether a bioactive constituent extracted from the Chinese herb Leonurus japonicus Houtt. (Yimucao), stachydrine, could improve cardiac function by inhibiting myocardial ferroptosis. We found significant morphological features of ferroptosis in a TAC-induced mouse model of heart failure, in which increased lipid peroxidation in cardiac tissue was accompanied by abnormalities in cystine metabolism as well as iron metabolism. The contractile function of adult mouse cardiomyocytes was severely reduced after the occurrence of erastin-induced ferroptosis. We found that in heart failure mice and erastin-induced cardiomyocyte ferroptosis models, stachydrine significantly improved myocardial function, improving mitochondrial morphological features of ferroptosis and associated signaling pathway alterations, including lipid peroxidation levels, cystine metabolism, and iron metabolism. The results of studies on stachydrine provides new inspirations for the treatment of cardiac ferroptosis and chronic heart failure.