Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition

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 aMHC-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.

Yunchang Liu, Liping Zeng, Yong Yang, Chen Chen, Daowen Wang, Hong Wang