KLF9 Aggravates Doxorubicin-Induced Cardiotoxicity by Regulating the ROS/p53 Signalling Pathway

Doxorubicin (DOX) is a cytotoxic chemotherapeutic drug, the clinical value of which is limited by its cardiotoxicity. Krüppel-like factor 9 (KLF9) is known to modulate cell proliferation, differentiation, and apoptosis and plays critical roles in cardiovascular diseases. Here, we aimed to explore the potential effect of KLF9 on DOX-induced cardiotoxicity. C57BL/6J mice with cardiac-specific overexpression or silencing of KLF9 received single intraperitoneal injections of DOX to establish a DOX-induced cardiotoxicity model. The cardiac function of the mice was monitored by echocardiography, cardiac morphology was evaluated by histopathological staining, biomarkers of myocardial injury were detected using ELISA, and TUNEL staining and Western blotting were performed to evaluate apoptosis. In addition, H9c2 cells were used to validate the function of KLF9 in vitro. To test the involvement of thioredoxin reductase 2 (Txnrd2), ROS and p53 in the observed effects, siRNAs directed against p53 and Txnrd2 and the ROS inhibitor N-acetyl cysteine (NAC) were used. KLF9 expression was upregulated in the hearts of DOX-treated mice and H9c2 cells. Cardiac-specific KLF9 overexpression exacerbated, while cardiac-specific KLF9 silencing alleviated, DOX-induced apoptosis, acute myocardial injury and dysfunction. Mechanistically, KLF9 deficiency resulted in upregulation of Txnrd2 expression and subsequent suppression of apoptosis through modulation by ROS/p53 signalling. KLF9 exerts a pro-apoptotic effect on DOX-induced cardiotoxicity by inhibiting Txnrd2 and regulating the ROS/p53 signalling pathway. KLF9 deficiency may be a promising target for mitigating DOX-induced cardiotoxicity.