Activation of the ERRa 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 (ERRa) is a key regulator of energy metabolism, especially in tissues with high energy demands. Here, we demonstrate that ERRa acts as a beneficial modulator of mitochondrial metabolism in anthracycline-induced cardiotoxicity (AIC). ERRa gain-of-function enhances cardiomyocyte metabolism and mitochondrial function, thereby alleviating AIC. Conversely, cardiomyocyte-specific knockdown of ERRa exacerbates mitochondrial bioenergetic collapse and worsens heart failure phenotypes in AIC mice. Additionally, our research identifies a top-ranking isoflavone phytoestrogen as a novel ERRa agonist with favorable pharmacological properties. This compound promotes the transcriptional activity of metabolic genes, representing a significant step toward developing natural ERRa agonists for AIC therapy. Overall design: RNA-seq profiling of cardiac tissue of miniature pigs from control group, Dox group and Dox+Formononetin group.