Androgen receptor alleviates doxorubicin-induced endoplasmic reticulum stress and myocardial injury by interacting with SERCA2a

Abstract

The clinical use of the anticancer drug doxorubicin (DOX) is limited due to its time- and dose-dependent cardiotoxicity. Therefore, there is an urgent need to explore the molecular mechanism and coping strategies for alleviating DOX-induced cardiotoxicity (DIC) and solve the difficulties in clinical application. The role and mechanism of androgen receptor (AR), which is the target of androgen, in DIC remain unclear. Here, we elucidated the molecular mechanisms of AR in DOX-induced cardiotoxicity. Inhibition of AR aggravated the DOX-induced cardiac function impairment, while the activation of AR showed obvious therapeutic effect and rescued cardiac function of rats. AR can physically interact with SERCA2a. Activation of AR participates in the regulation of DOX-induced myocardial injury by modulating SERCA2a, attenuating DOX-induced endoplasmic reticulum stress, improving calcium (Ca²⁺) cycling homeostasis, and inhibiting ROS levels and apoptosis, thereby participating in the regulation of DOX induced myocardial injury. Altogether, these findings reveal for the first time the relationship and role between AR and SERCA2a in regulating the progression of DIC, suggesting that AR may play a therapeutic role as a new target against DIC.