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 (ISO)-induced myocardial hypertrophy in mice was associated with 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 enhanced glucocorticoid receptor (GR)-mediated upregulation of heat shock protein 70 (HSP70), which in turn activated pro-hypertrophic AKT signaling. Adenoviral SRA overexpression in H9C2 cardiomyocytes amplified ISO-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.