Activation of the ERRα Transcriptional Pathway Alleviates Anthracycline-induced Cardiotoxicity by Improving Mitochondrial Metabolism

Anthracycline-induced metabolic remodeling and mitochondrial damage are critical early events that contribute to cardiac dysfunction. However, the gene regulatory pathways governing the derangements in myocardial bioenergetics have not yet been fully delineated. Estrogen-related receptor alpha (ERRα) is a key regulator of energy metabolism, especially in tissues with high energy demands. Here, we demonstrate that ERRα acts as a beneficial modulator of mitochondrial metabolism in anthracycline-induced cardiotoxicity (AIC). ERRα gain-of-function enhances cardiomyocyte metabolism and mitochondrial function, thereby alleviating AIC. Conversely, cardiomyocyte-specific knockdown of ERRα exacerbates mitochondrial bioenergetic collapse and worsens heart failure phenotypes in AIC mice. Additionally, our research identifies a top-ranking isoflavone phytoestrogen as a novel ERRα agonist with favorable pharmacological properties. This compound promotes the transcriptional activity of metabolic genes, representing a significant step toward developing natural ERRα agonists for AIC therapy. RNA-seq profiling of cardiac tissue of miniature pigs from control group and Dox group.