Ginkgetin enhances breast cancer radiotherapy sensitization by suppressing NRF2-HO-1 axis activity.

Breast cancer (BC) is a critical threat to women's lives. Radiotherapy (RT) is a pivotal treatment modality for BC, but the failure of RT due to radioresistance is still not well facilitated. Ginkgetin (GK) has a potent anti-tumor activity intimately associated with ferroptosis. This study applied in vitro and in vivo experimental models to ascertain the GK mechanism of action on BC radioresistance. The outcomes reported that GK could inhibit BC cell growth and increase apoptosis. In addition, when BC cells generated radioresistance, GK promoted ferroptosis of radioresistant BC cells by mitigating NRF2 expression, suppressing HO-1 and NQO1 expression, increasing the intracellular content of reactive oxygen species (ROS) and ferrous ions, accelerating the glutathione (GSH) depletion, and decreasing GPX4 expression. Notably, GK can damage intracellular mitochondria and cause a substantial increase in ferrous ions in BC cells. Therefore, GK shows immense potential for enhancing breast cancer radiotherapy sensitivity, which may provide pivotal evidence for subsequent RT sensitization.