Concomitant Administration of Dantrolene is Sufficient to Protect Against Doxorubicin-Induced Cardiomyopathy

Doxorubicin (DOX), a commonly used anticancer agent, can result in cardiac dysfunction, presenting a significant clinical challenge. DOX has been shown to induces Ca 2+ leakage via the ryanodine receptor 2 (RYR2) of the sarcoplasmic reticulum, increasing Ca 2+ levels in the cytoplasm. This study investigated whether stabilizing RYR2 could suppress DOX-induced cardiomyopathy (DIC) and identified the optimal duration of dantrolene treatment as a pharmacological method. We investigated the effects of RYR2 stabilization on DOX cardiotoxicity using in vivo and in vitro experiments. DOX administration caused calmodulin dissociation, marked Ca 2+ leakage from RYR2, and increased oxidative stress in isolated cardiomyocytes. Stabilizing the RYR2 tetramer—either pharmacologically with dantrolene or genetically via RYR2 V3599K mutation, which enhances calmodulin binding affinity—suppressed these effects. In DIC mice models, DOX impaired cardiac function, increased fibrosis and TUNEL-positive cells, reduced GRP78, and elevated lipid peroxide levels, leading to endoplasmic reticulum stress and ferroptosis. Both continuous dantrolene treatment and RYR2 V3599K mutation improved cardiac function. Interestingly, dantrolene administration provided myocardial protection even when terminated 7 days after DOX. Short-term concomitant use of dantrolene offers a promising and clinically feasible strategy to prevent DIC. Given dantrolene’s established clinical safety as a treatment for malignant hyperthermia, these findings suggest potential for repositioning dantrolene in DIC prevention.