Trim65 mitigates doxorubicin-induced myocardial injury by reducing ferroptosis.

BACKGROUND AND AIMS

The anthracycline chemotherapeutic agent doxorubicin (DOX) is widely used to treat cancer. However, DOX carries a high risk of adverse effects such as cardiovascular events. The aim of this study was to explore the role of Trim65 in DOX-induced cardiotoxicity (DIC) and its underlying mechanisms.

METHODS AND RESULTS

Cellular studies were performed by exposing H9c2 cells (rat cardiomyocytes) to DOX. H9c2 cells were infected with lentivirus encoding negative control (LV-NC) or Trim65 (LV-Trim65). C57BL/6J mice were exposed to adeno-associated virus 9 (AAV9) containing cTnT promoter-encoded Trim65 sequence (AAV-Trim65) or AAV9 negative control sequence (AAV-NC) via tail vein injection. Furthermore, the following analysis were performed: cell viability, intracellular ROS production and lipid peroxidation. Echocardiography was used to measure the heart function of the mice. qPCR and western blotting were used to assess the expression of Trim65, p53, SLC7A11, and GPX4. According to our study, Trim65 expression was significantly downregulated in DIC. Overexpression of Trim65 exhibited considerable protection against to DIC, confirmed by both in vitro and in vivo experiments. In DOX-treated mice, mitochondria deformation was observed in the heart, as well as a high level of lipid peroxidation (signs of ferroptosis) and iron content, which were mitigated by overexpression of Trim65. Mechanistically, our study confirmed that DOX reduced the Trim65-mediated ubiquitination of p53, ultimately inhibiting the degration of p53. We also found that Trim65 mitigated DOX-induced ferroptosis via p53.

CONCLUSION

Collectively, our data demonstrated that Trim65 inhibits ferroptosis by degrading p53, thereby alleviating DIC. Therefore, Trim65 could be a promising target for the treatment of DIC.