2. Academic Validation
  3. Sacubitril/Valsartan partially alleviates myocardial infarction injury by activating the FGF21 signaling pathway via PPARs

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

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. cwang@wmu.edu.cn.
  • 5 Department of Clinical Research, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, 311200, Zhejiang, China. xuebopan@wmu.edu.cn.
  • 6 School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, 325035, Zhejiang, China. xuebopan@wmu.edu.cn.
  • # 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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