Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell–derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.

多柔比星是一种常用的抗癌剂，可导致衰弱和不可逆的心脏损伤。导致这种副作用的起始机制仍然未知，目前的预防策略只能提供适度的保护。使用来自接受阿霉素的患者的干细胞衍生的心肌细胞，我们探索了溶质载体的转录组学，并确定有机阳离子转运蛋白 3 (OCT3) (SLC22A3) 是调节多柔比星心脏积累的关键转运蛋白。异源过表达模型中的功能验证研究证实，多柔比星通过 OCT3 转运到心肌细胞中，并且 OCT3 的缺乏保护小鼠免受与心脏损伤相关的心血管功能和遗传途径的急性和慢性多柔比星相关变化。为了提供原理证明并证明这种转运机制的转化相关性，我们确定了几种 OCT3 的药理学抑制剂，包括尼罗替尼，并发现 OCT3 的药理学靶向也可以在多柔比星治疗后保持心血管功能而不影响其血浆水平或抗肿瘤在多种白血病和乳腺癌模型中的影响。最后，我们确定了一个以前未被认识的、OCT3 依赖性多柔比星诱导的心脏毒性通路，该通路导致涉及钙结合蛋白 S100A8 和 S100A9 的下游信号级联反应。这些集体发现不仅揭示了多柔比星引起的心脏毒性的病因，