The Drp1 inhibitor DRP1i2 confers cardioprotection against doxorubicin-induced cardiotoxicity

Abstract Anthracyclines such as doxorubicin are highly effective chemotherapeutic agents, but their clinical use is limited by dose-dependent cardiotoxicity associated with mitochondrial dysfunction. Dysregulated mitochondrial dynamics, particularly excessive dynamin-related protein 1 (Drp1)-mediated fission, has been implicated in cardiac injury. We investigated whether DRP1i2, a novel small-molecule Drp1 inhibitor targeting a conserved domain, mitigates doxorubicin-induced cardiotoxicity while preserving anticancer efficacy. Cardioprotective effects were assessed in a murine model of chronic doxorubicin cardiotoxicity and in human induced pluripotent stem cell-derived cardiac microtissues, while anticancer activity was evaluated across multiple cancer cell lines in 2D and 3D systems. DRP1i2 preserved left ventricular systolic function in vivo, reduced interstitial fibrosis and cardiomyocyte atrophy, and attenuated myocardial proteomic remodelling. In human cardiac microtissues, DRP1i2 improved viability and restored contractile function despite persistent mitochondrial oxidative stress and metabolic dysfunction. In cancer models, DRP1i2 did not compromise doxorubicin efficacy across A549 lung cancer, OVCAR3 ovarian cancer, and MDA-MB-231 breast cancer cell lines, and exhibited modest anticancer activity in MG63 osteosarcoma cells. These findings demonstrate that DRP1i2 confers cardioprotection while maintaining anticancer efficacy via modulation of Drp1-dependent mitochondrial dynamics, supporting mitochondrial fission as a targetable pathway to mitigate doxorubicin-induced cardiotoxicity.