2. Academic Validation
  3. Targeting steroid receptor RNA activator as a novel therapeutic strategy for myocardial hypertrophy

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

  • Biochem Pharmacol. 2025 Oct:240:117121. doi: 10.1016/j.bcp.2025.117121.
Weichun Qian 1,  Zhuoqun Liu 2,  Wen Zhang 2,  Luyao Yang 2,  Yifan Zhang 2,  Wenjun Liu 2,  Ling Tao 3,  Bin Xu 4,  Liang Sheng 5,  Xiangchun Shen 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
  • 2 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 3 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang and Guian New District, Guizhou 561113, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang and Guian New District, Guizhou 561113, China.
  • 4 Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI 48109-56788, USA. Electronic address: bxu@umich.edu.
  • 5 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Electronic address: lgsheng@njmu.edu.cn.
  • 6 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang and Guian New District, Guizhou 561113, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang and Guian New District, Guizhou 561113, China. Electronic address: sxc@gmc.edu.cn.
PMID: 40619012 DOI: 10.1016/j.bcp.2025.117121
Abstract

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.

Keywords

Glucocorticoid receptor; Heat shock protein 70; Myocardial hypertrophy; Phosphatidylinositol–4,5–bisphosphate 3–kinase/AKT pathway; Steroid receptor RNA activator.

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