2. Academic Validation
  3. METTL3-mediated N6-methyladenosine modification contributes to vascular calcification

METTL3-mediated N6-methyladenosine modification contributes to vascular calcification

  • J Mol Cell Cardiol. 2025 Jun:203:22-34. doi: 10.1016/j.yjmcc.2025.04.006.
Long Li 1,  Quanyou Chai 1,  Chunling Guo 2,  Junyi Wei 3,  Yuqiao Qin 3,  Huimin Liu 4,  Zhaoyang Lu 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Hangzhou, China; Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou, China; Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
  • 2 Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
  • 3 Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
  • 4 Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China. Electronic address: flysharon@zju.edu.cn.
  • 5 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Hangzhou, China; Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou, China; Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, China. Electronic address: luzhaoyang@zju.edu.cn.
PMID: 40222552 DOI: 10.1016/j.yjmcc.2025.04.006
Abstract

Aim: Vascular calcification (VC) is a major adverse cardiovascular event in chronic kidney disease (CKD) patients. N6-methyladenosine (m6A) modification is vital for many biological processes, but its function and possible molecular mechanisms in VC are poorly understood. This study aimed to clarify the function and molecular mechanisms of N6-adenosine-methyltransferase-like 3 (METTL3) in VC.

Methods and results: The results of the bioinformatic analysis showed that METTL3 expression was significantly upregulated in calcified VSMCs. This finding was corroborated by phosphate-induced VSMCs calcification models and 5/6 nephrectomy-induced CKD mouse VC models. Afterward, Alizarin Red S staining and m6A dot blot analysis demonstrated METTL3 overexpression elevated m6A levels and encouraged calcification in VSMCs and mouse aortic rings, while METTL3 knockdown decreased m6A levels and inhibited calcium deposition in these experimental models. Furthermore, METTL3 promoted VC via the PTEN/Akt pathway, and MeRIP verified that METTL3 induced PTEN mRNA degradation by modifying it with m6A. In addition, molecular docking simulations and DARTS assays revealed that quercetin is a natural small-molecule inhibitor of METTL3. The current investigation demonstrated that quercetin mitigated VC by reducing METTL3-dependent m6A levels in vivo and in vitro.

Conclusion: In conclusion, this study unraveled the pathogenic mechanism of METTL3-mediated m6A modification in VC and provided new insights to establish METTL3 as a therapeutic target for VC.

Keywords

Inhibitor; METTL3; Quercetin; Vascular calcification; m6A modification.

Figures
Products