Liposome doxorubicin attenuates cardiotoxicity by reducing ferritinophagy

Background Doxorubicin (DOX) is widely used in lymphoma, myeloma, breast cancer, and other malignant tumors, and it significantly improves the prognosis of these patients. However, its side effects, especially cardiotoxicity, must be taken seriously. Studies have shown that liposome doxorubicin (L-DOX), compared with DOX, has increased anti-tumor activity and decreased cardiac toxicity. Our aim is to investigate the mechanism of myocardial injury in mice caused by these two drugs, to identify potential mitigation strategies. Methods In this study, mice or HL-1 cells were treated with DOX or L-DOX, and the cardiac morphology, hemodynamic effect, laboratory examination, and expression of ferritinophagy-related proteins were compared with the control group. Results DOX significantly induced myocardial cell death, while L-DOX had little effect on myocardial injury. Additionally, DOX significantly increased the level of autophagy and ferroptosis in cardiac myocytes. Further analysis revealed that NCOA4-mediated ferritinophagy played a key role in the mechanism of doxorubicin-induced cardiotoxicity (DIC). Importantly, the addition of ferrostatin-1 (a ferroptosis inhibitor) was able to rescue DIC. In contrast, L-DOX reduced the damage to cardiac myocytes by reducing ferritinophagy. Conclusion We have found that a significant relationship between the mechanism of DIC and NCOA4-mediated ferritinophagy. L-DOX has been shown to reduce the damage to myocardial cells by reducing NCOA4-mediated ferritinophagy. Thus, NCOA4 has the potential to be a drug target for the cardiac protection of DIC. However, further research is need to investigate the specific role of NCOA4 in the pathogenesis of DIC.