In this study, we first established the doxorubicin-induced cardiotoxicity (DIC) model with C57BL/6 mice and confirmed cardiac dysfunction with transthoracic echocardiography examination. RNA-sequencing was then performed to explore the potential mechanisms and transcriptional changes in the process. The metabolic pathway, biosynthesis of polyunsaturated fatty acid was significantly altered in DOX-treated murine heart, and Acot1 was one of the leading-edge core genes. We then investigated the role of Acot1 to ferroptosis that was reported recently to be related to DIC. The induction of ferroptosis in the DOX-treated heart was confirmed by transmission electron microscopy, and the inhibition of ferroptosis using Fer-1 effectively prevented the cardiac injury as well as the ultrastructure changes of cardiomyocyte mitochondrial. Both in vitro and in vivo experiments proved the downregulation of Acot1 in DIC, which can be partially prevented with Fer-1 treatment. Overexpression of Acot1 in cell lines showed noteworthy protection to ferroptosis, while the knock-down of Acot1 sensitized cardiomyocytes to ferroptosis by DIC. Finally, the heart tissue of αMHC-Acot1 transgenic mice presented altered free fatty acid composition, indicating that the benefit of Acot1 in the inhibition of ferroptosis lies biochemically and relates to its enzymatic function in lipid metabolism in DIC. The current study highlights the importance of ferroptosis in DIC and points out the potential protective role of Acot1 in the process. The beneficial role of Acot1 may be related to its biochemical function by shaping the lipid composition. In all, Acot1 may become a potential treating target in preventing DIC by anti-ferroptosis.

在这项研究中，我们首先用 C57BL/6 小鼠建立了阿霉素诱导的心脏毒性 (DIC) 模型，并通过经胸超声心动图检查证实了心脏功能障碍。然后进行 RNA 测序以探索该过程中的潜在机制和转录变化。在 DOX 处理的小鼠心脏中，多不饱和脂肪酸的代谢途径、生物合成发生了显着改变，Acot1 是前沿的核心基因之一。然后我们研究了 Acot1 对最近报道的与 DIC 相关的铁死亡的作用。透射电子显微镜证实了 DOX 处理心脏中铁死亡的诱导，使用 Fer-1 抑制铁死亡有效地防止了心脏损伤以及心肌细胞线粒体的超微结构变化。体外和体内实验都证明了 DIC 中 Acot1 的下调，这可以通过 Fer-1 治疗部分预防。Acot1 在细胞系中的过表达显示出对铁死亡的显着保护，而 Acot1 的敲低使心肌细胞对 DIC 的铁死亡敏感。最后，αMHC-Acot1 转基因小鼠的心脏组织呈现出改变的游离脂肪酸组成，表明 Acot1 在抑制铁死亡方面的益处在于生化方面，并与其在 DIC 脂质代谢中的酶功能有关。目前的研究强调了铁死亡在 DIC 中的重要性，并指出了 Acot1 在该过程中的潜在保护作用。Acot1 的有益作用可能与其通过塑造脂质组成的生化功能有关。在所有，