Estrogen-related receptors are targetable ROS sensors

Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Herein, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRa downregulation restricts glutamine entry into the TCA cycle while ERR? upregulation promotes glutamine-driven glutathione production. Notably, we identify increased ERR? expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERR? with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERR? inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role. In this study, ERR? ChIP-seq analysis was performed under normal conditions in the breast cancer cell line BT-474. Overall design: Duplicate ChIP-seq experiments of ERRgamma (ERR?, ESRRG) were performed in BT-474 breast cancer cells under basal conditions with input DNA as a control ChIP-seq.