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

Signal Transduction and Targeted Therapy ARTICLE www.nature.com/sigtrans OPEN Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models 1234567890();,: Ke Xiong1,2, Guanghua Wang1,2,3, Desheng Li 1,2, Beihua Shao1,2,3, Zhiwen Chen1,2,3, Qicheng Zou1,2, Xinrui Zhang4, Yanru Dong1, Xuxia Zhao1, Yixin Yuan1, Hongtao Xu1, Yi Liu1,2,3, Dandan Liang1,2,3, Li Wang 5, Bin Zhou 6, Nianguo Dong 7 ✉, Duanyang Xie1,2,3 ✉ and Yi-Han Chen 1,2,3,8 ✉ 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. Signal Transduction and Targeted Therapy (2026)11:105 INTRODUCTION Atrial fibrillation (AF), the most common form of sustained cardiac arrhythmia, continues to rise globally, currently affecting more than 60 million individuals and placing a significant burden on healthcare systems both clinically and economically.1,2 Global burden-of-disease analyses indicate a steady increase in disabilityadjusted life years attributable to AF.1 This trend is largely attributed to population aging, extended life expectancy, and persistent exposure to chronic yet modifiable risk factors, with improved detection further exacerbating the observed rise. Longterm follow-up studies of prospective cohorts highlight the ongoing challenge of mitigating the health consequences of AF.1 Collectively, these analyses underscore the need for research on AF beyond rhythm control, emphasizing the identification of upstream biological mechanisms that can be targeted therapeutically. The pathophysiology of AF is tightly intertwined with the dysregulation of Ca2+ handling in atrial cardiomyocytes.3,4 For instance, aberrant Ca2+ leakage through ryanodine receptor type 2 (RyR2) can provoke spontaneous Ca2+ release events, subsequently activating the sodium-calcium exchanger (NCX), thereby ; https://doi.org/10.1038/s41392-026-02615-6 depolarizing the membrane potential and initiating delayed afterdepolarizations (DADs).4–6 Furthermore, sustained Ca2+ overload combined with Na+ accumulation drives NCX reverse-mode activation, exacerbating Ca2+ influx and cytoplasmic Ca2+ accumulation, ultimately lowering the threshold for ectopic (triggered) activity and contributing to the initiation of AF.6–9 While the mechanistic link between abnormal Ca2+ handling and AF is well-established, the upstream molecular hierarchy that initiates this pathological cascade has not been fully explored, presenting a critical barrier to the development of targeted therapies. To address this, we employed an integrated multi-omics approach, combining single-cell RNA sequencing, bulk RNA sequencing, and functional Ca2+ dynamics analysis in atrial cardiomyocytes from human AF patients and rodent AF models. This approach allowed us to correlate molecular alterations with functional Ca2+ aberrancies and AF pathogenesis, ultimately leading to the identification of visinin-like protein 1 (VILIP-1) as a key candidate regulator of Ca2+ homeostasis in AF. VILIP-1 belongs to the neuronal Ca2+ sensors (NCSs), a diverse family of Ca2+-binding proteins that participate in Ca2+-dependent signaling and mediate various cellular responses across different 1 State Key Laboratory of Cardiovascular Diseases and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; 2Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; 3Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China; 4Jinzhou Medical University, Liaoning, China; 5State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 6Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; 7Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and 8Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China Correspondence: Nianguo Dong () or Duanyang Xie () or Yi-Han Chen () These authors contributed equally: Ke Xiong, Guanghua Wang, Desheng Li, Beihua Shao, Zhiwen Chen Received: 7 May 2025 Revised: 25 December 2025 Accepted: 27 January 2026 © The Author(s) 2026 Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial. . . Xiong et al. 2 tissues.10 In neurons, they increase synaptic plasticity and neurotransmitter release; in pancreatic cells, they promote insulin secretion; and in skin, they suppress the invasiveness of squamous cell carcinoma cells.10–14 Upon Ca2+ binding, VILIP-1 undergoes a conformational change, exposing its myristoyl group and facilitating translocation to the plasma membrane.15 This Ca2+dependent translocation enhances VILIP-1’s interaction with target proteins, which increases their surface expression and activates specific signaling pathways. However, the role of VILIP-1 in the heart, particularly in atrial cardiomyocytes and AF, has remained underexplored. In this study, we reveal a previously unprecedented association between VILIP-1 upregulation and AF in both human patients and animal models. Our findings demonstrate that VILIP-1 regulates Ca2+ homeostasis in atrial cardiomyocytes by modulating the surface expression of NCX-1 in a (...truncated)