Palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis: A new target for anti-myocardial fibrosis

  • Acta Pharm Sin B. 2025 Sep;15(9):4789-4806. doi: 10.1016/j.apsb.2025.07.011.
Xuewen Yang  1  2 ,  Yanwei Zhang  1 ,  Xiaoping Leng  3 ,  Yanying Wang  1 ,  Manyu Gong  4 ,  Dongping Liu  1 ,  Haodong Li  1 ,  Zhiyuan Du  1 ,  Zhuo Wang  3 ,  Lina Xuan  1 ,  Ting Zhang  5 ,  Han Sun  1 ,  Xiyang Zhang  1 ,  Jie Liu  1 ,  Tong Liu  1 ,  Tiantian Gong  1 ,  Zhengyang Li  1 ,  Shengqi Liang  1 ,  Lihua Sun  1 ,  Lei Jiao  1 ,  Baofeng Yang  1  6 ,  Ying Zhang  1  7
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 Pharmacology, Institute of Pharmacokinetics and Liver Molecular Pharmacology, Baotou Medical College, Baotou 014040, China.
  • 3. Department of Ultrasound Imaging, the Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin 150086, China.
  • 4. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
  • 5. Department of Inorganic Chemistry and Physical Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 6. Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin 150081, China.
  • 7. Ultrasound Imaging Department of the Second Affiliated Hospital of Harbin Medical University, and State-Province Key Laboratories of Biomedicine-Pharmaceutics, College of Pharmacy of Harbin Medical University, Harbin 150081, China.
PMID: 41049740 DOI: 10.1016/j.apsb.2025.07.011
Abstract

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes Collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Keywords
Anti-cardiac fibrosis; Berberine chloride; Collagen synthesis; Fibrosis after myocardial infarction; P4HA1; Palmitoylation; Post-translational modification; SARM1.
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