CTRP4 overexpression mitigates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and ferroptosis through activation of the Sirt1-Nrf2 signaling axis.

Oxidative stress and ferroptosis are major drivers of doxorubicin (DOX)-induced cardiotoxicity. C1q/TNF-related protein 4 (CTRP4) is an endogenous cardioprotective factor that modulates both processes; however, its role and underlying mechanisms in DOX-induced myocardial injury remain unclear. We hypothesized that CTRP4 serves as a novel endogenous regulator protecting against DOX cardiotoxicity and investigated its function and molecular pathways. A mouse model of DOX-induced cardiotoxicity, with saline-treated animals as controls, and H9c2 cells were used for in vitro validation. Morphological analyses, western blotting, and RNA sequencing revealed that DOX markedly downregulated CTRP4 expression. CTRP4 overexpression attenuated DOX-induced cardiac remodeling, reduced iron, MDA, and ROS levels, and increased GSH levels and GPx4 expression, thereby suppressing ferroptosis in vivo and in vitro, with effects comparable to those of the ferroptosis inhibitor Fer-1. Conversely, CTRP4 knockdown exacerbated DOX-induced oxidative stress and ferroptosis. Mechanistically, CTRP4 activated the Sirt1/Nrf2 pathway, whereas Sirt1 or Nrf2 silencing completely abolished its protective effects against DOX injury. Collectively, CTRP4 attenuates DOX cardiotoxicity by suppressing oxidative stress and ferroptosis through the Sirt1/Nrf2 axis, highlighting its therapeutic potential for DOX-induced cardiac injury.