2. Academic Validation
  3. RBMS1 orchestrates cardiac hypertrophy by facilitating CTTN splice-switching and sarcomere dynamics

RBMS1 orchestrates cardiac hypertrophy by facilitating CTTN splice-switching and sarcomere dynamics

  • EMBO Mol Med. 2025 Dec;17(12):3555-3585. doi: 10.1038/s44321-025-00334-z.
Liangliang Li # 1,  Tianyu Li # 1,  Bin Wang # 2,  Jiayue Feng # 1,  Nan Zhang 3,  Jing Zhang 1,  Zhihui Niu 1,  Wei Li 1,  Huiying Gao 1,  Qianqian Wang 1,  Yang Liu 1,  Yi Chen 1,  Yixin Zhang 1,  Yu Bian 1,  Tengfei Pan 1,  Siqi Sheng 4,  Xuelian Li 1,  Jinping Liu 5,  Baofeng Yang 6 7,  Haihai Liang 8 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 2 Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 3 Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
  • 4 The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 5 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China. [email protected].
  • 6 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. [email protected].
  • 7 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. [email protected].
  • 8 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. [email protected].
  • 9 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. [email protected].
  • 10 Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, 150081, Harbin, China. [email protected].
  • # Contributed equally.
PMID: 41214391 DOI: 10.1038/s44321-025-00334-z
Abstract

Cardiac hypertrophy is one of the significant causes of heart failure and is closely related to the rising rate of hospitalization and readmissions. Given the diverse regulatory roles of alternative splicing in cardiovascular diseases, RNA-binding proteins have attracted increasing research attention. Here, for the first time, we discovered elevated expression of RBMS1 in heart tissues of patients with dilated cardiomyopathy and in mice with cardiac hypertrophy. We demonstrated that RBMS1 activated the PI3K/Akt signaling pathway by promoting the splicing CTTN to generate CTTN-Δe11 splicing isoform, resulting in Cytoskeleton and sarcomere damage in cardiomyocytes. Additionally, pharmacological inhibition of RBMS1 by nortriptyline alleviated cardiac hypertrophy and heart failure. These results provide a new perspective for developing novel therapeutic approaches for cardiac hypertrophy and establish a theoretical basis for targeting RBMS1 in the clinical treatment of cardiac hypertrophy.

Keywords

Alternative Splicing; CTTN; Cardiac Hypertrophy; RBMS1; Sarcomere.

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