Sacubitril/Valsartan partially alleviates myocardial infarction injury by activating the FGF21 signaling pathway via PPARs

  • Cardiovasc Diabetol. 2025 Feb 22;24(1):89. doi: 10.1186/s12933-025-02627-6.
Wenjuan Wei  #  1 ,  Guangsen Xu  #  2 ,  Jiaer Gao  1 ,  Guiyun Wang  2 ,  Ye Wang  2 ,  Caiyan Li  1 ,  Junwei Zheng  2 ,  Huiying Lu  2 ,  Yunyan Lu  1 ,  Kun Wang  2 ,  Hongtao Xu  3 ,  Cong Wang  4 ,  Xuebo Pan  5  6
Affiliations
  • 1. Department of Clinical Research, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, 311200, Zhejiang, China.
  • 2. School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, 325035, Zhejiang, China.
  • 3. Lishui Central Hospital, The Fifth Hospital Affiliated to Wenzhou Medical University, LiShui, 323000, Zhejiang, China.
  • 4. School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, 325035, Zhejiang, China. [email protected].
  • 5. Department of Clinical Research, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, 311200, Zhejiang, China. [email protected].
  • 6. School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, 325035, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 39987117 DOI: 10.1186/s12933-025-02627-6
Abstract

The recent discovery of clinically significant data, alongside novel physiological and pathological occurrences surrounding sacubitril/valsartan (Sac/Val) beyond its approved indications, necessitates an urgent reevaluation of its underlying mechanism of action. In the present investigation, we observed a substantial elevation in the serum levels of Fibroblast Growth Factor 21 (FGF21) among patients with acute myocardial infarction (AMI) who were administered Sac/Val, compared to those who were not, utilizing ELISA-based measurements. Furthermore, through the utilization of a mouse model of myocardial infarction induced by ligation of the left anterior descending branch, we confirmed that FGF21 mediates the cardioprotective effect of Sac/Val, employing both loss-of-function and gain-of-function approaches. Molecular docking and SPR experiments validated that Sac/Val can regulate FGF21 via its interaction with PPARs, and verified the role of PPARs in mediating Sac/Val regulation of FGF21 by inhibiting PPARs. In conclusion, we found that Sac/Val can act as an agonist of FGF21, which provides a new idea for the development of FGF21 drugs, and FGF21 as a new target of Sac/Val to ameliorate myocardial infarction, which provides a basis for new indications for Sac/Val.

Keywords
Fibroblast growth factor 21; Myocardial infarction; Peroxisome proliferation-activated receptor alpha; Peroxisome proliferation-activated receptor gamma; Sacubitril/Valsartan.
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