Targeting steroid receptor RNA activator as a novel therapeutic strategy for myocardial hypertrophy

Myocardial hypertrophy develops when the heart is subjected to biomechanical stress, neurohormonal or hemodynamic stimuli. Isoprenaline-induced myocardial hypertrophy in mice exhibited abnormally elevated steroid receptor RNA activator (SRA) level in hypertrophic myocardium, suggesting SRA’s potential functions in hypertrophic pathogenesis. SRA knockout or cardiac-specific knockdown attenuated cardiac remodeling without impairing baseline cardiac function. RNA sequencing and mechanistic studies identified SRA as a transcriptional coactivator that enhances GR-mediated upregulation of HSP70, which in turn activates pro-hypertrophic Akt signaling. Adenoviral SRA overexpression in H9C2 cardiomyocytes amplified isoprenaline-triggered hypertrophic gene expression via this GR-HSP70-Akt axis. Those findings establish SRA as a stress-responsive regulator of maladaptive cardiac growth and propose SRA inhibition as a targeted therapeutic strategy for hypertrophy-related cardiomyopathy. This work bridges noncoding RNA biology with metabolic signaling in heart disease, offering both mechanistic insights and translational potential.