Aims Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF. Methods and results The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. Conclusion Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.

中文翻译：

---

来自胰岛素受体基因座的环状 RNA 可防止阿霉素诱导的心脏毒性

导致心力衰竭 (HF) 的心脏毒性是许多癌症幸存者中日益严重的问题。由于没有特定的治疗策略，因此采用了 RNA 发现管道，并开发了一种新的、强大的基于环状 RNA (circRNA) 的疗法来治疗多柔比星诱导的 HF。方法和结果 应用 circRNA 测序并鉴定了高度物种保守的 circRNA 胰岛素受体 (Circ-INSR)，它参与 HF 过程，包括那些由心脏毒性抗癌治疗引起的过程。化疗引起的心脏毒性导致啮齿动物和患者的 Circ-INSR 下调，这在机制上导致心肌细胞死亡、心脏功能障碍和线粒体损伤。相比之下，Circ-INSR 过表达在体外和慢性多柔比星心脏毒性小鼠模型中阻止了多柔比星介导的啮齿动物和人类心肌细胞的心脏毒性。1 型乳腺癌易感蛋白 (Brca1) 被确定为 Circ-INSR 表达的调节剂。详细的转录组学和蛋白质组学分析表明，Circ-INSR 调节心肌细胞的凋亡和代谢途径。Circ-INSR 与单链 DNA 结合蛋白 (SSBP1) 发生物理相互作用，介导其在阿霉素应激下的心脏保护作用。重要的是，体外转录和环化的 Circ-INSR 模拟物还可以防止阿霉素诱导的心脏毒性。结论 Circ-INSR 是一种高度保守的非编码 RNA，在心脏毒性和心脏重构过程中下调。基于腺相关病毒和 circRNA 模拟物的 Circ-INSR 过表达可预防和逆转阿霉素介导的心肌细胞死亡并改善心脏功能。这项研究的结果强调了一种新颖且具有重要转化意义的基于 Circ-INSR 的阿霉素诱导的心功能障碍治疗方法。