Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models PMID: 41872178

ADC Targets in Oncology

2026-04-10

Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models

Signal Transduct Target Ther. 2026 Mar 23;11(1):105. doi: 10.1038/s41392-026-02615-6.

Ke Xiong ^# ¹ ² , Guanghua Wang ^# ¹ ² ³ , Desheng Li ^# ¹ ² , Beihua Shao ^# ¹ ² ³ , Zhiwen Chen ^# ¹ ² ³ , Qicheng Zou ¹ ² , Xinrui Zhang ⁴ , Yanru Dong ¹ , Xuxia Zhao ¹ , Yixin Yuan ¹ , Hongtao Xu ¹ , Yi Liu ¹ ² ³ , Dandan Liang ¹ ² ³ , Li Wang ⁵ , Bin Zhou ⁶ , Nianguo Dong ⁷ , Duanyang Xie ⁸ ⁹ ¹⁰ , Yi-Han Chen ¹¹ ¹² ¹³ ¹⁴

Affiliations

1. State Key Laboratory of Cardiovascular Diseases and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
2. Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
3. Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China.
4. Jinzhou Medical University, Liaoning, China.
5. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
6. Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
7. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
8. State Key Laboratory of Cardiovascular Diseases and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
9. Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
10. Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China. [email protected].
11. State Key Laboratory of Cardiovascular Diseases and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
12. Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
13. Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China. [email protected].
14. Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular CA²⁺ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating CA²⁺ signaling, yet its role in AF remains undefined. In this study, we integrated bulk RNA Sequencing, single-cell transcriptomics, and electrophysiological profiling from human AF patients and rodent AF models to identify VILIP-1 as a key mediator of CA²⁺ dysregulation in AF. VILIP-1 was significantly upregulated in atrial tissues from AF patients and in pacing-induced rat AF models, with enhanced membrane localization in cardiomyocytes. Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological CA²⁺ leakage, promoting delayed afterdepolarizations (DADs) and action potential duration (APD) alternans, which fostered AF substrate formation and increased arrhythmia susceptibility. Mechanistically, VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism, thereby disrupting CA²⁺ handling and initiating AF. Pharmacologically, repaglinide and desloratadine, two FDA-approved drugs that identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility by reducing NCX-1 surface expression and restoring intracellular CA²⁺ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial CA²⁺ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.