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.

PMID: 41872178 DOI: 10.1038/s41392-026-02615-6

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.

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