Thymidine exerts anti-doxorubicin-induced cardiomyopathy effect through the regulation of the PPAR signaling pathways and ferroptosis pathways

To evaluate the anti-cardiomyopathic activity of thymine (Thy) and to elucidate its mechanism of action. Transgenic zebra sh with enhanced green uorescent protein (EGFP)-labelled hearts (Tg (cmlc2: EGFP)) and wild-type AB zebrafish were used as experimental animals. A blank control group, a doxorubicin (DOX) model group, a dexrazoxane (DEX)-positive drug group and Thy drug treatment group were established. After treatment, indicators closely related to cardiac function, such as the pericardial area, heart rate, stroke volume, short-axis shortening (SAS) rate, and ejection fraction of the zebra sh in each group,were evaluated to determine the protective activity of Thy against DOX-induced cardiomyopathy. The pathways involved in the cardioprotective activity of Thy were analyzed via transcriptomics, and the regulatory effects of Thy on key genes were investigated using RT‒qPCR. The results indicated that Thy effectively relieved DOX-induced pericardial edema; reversed the effects of DOX on heart rate, stroke volume, SAS rate, ejection fraction, and blood velocity; and relieved DOX-induced myocardial ischemia, myocardial cell apoptosis and pathological structural changes in heart tissues. The transcriptome results indicated that the PPAR signaling and ferroptosis pathways were involved in the anti-DOX-induced cardiomyopathy effect of Thy. The RT‒qPCR results revealed that Thy regulated the mRNA expression levels of genes related to the PPAR signaling pathway and ferroptosis pathway (such as pparg, apoa1a, acsl5, pltp, and tfa). Thy may exert its anti-DOX-induced cardiomyopathy effect through the regulation of the PPAR signaling and ferroptosis pathways.