Wenxin Granules Prevent Ibrutinib‐Associated Atrial Fibrillation Through Restoring Redox Balance and Calcium Homeostasis

ABSTRACT Background Ibrutinib, a frontline therapy for chronic lymphocytic leukemia (CLL), has been associated with an approximately 10‐fold increased risk of atrial fibrillation (AF) during treatment. Wenxin Granules, as a multi‐component and multi‐target drug, exert therapeutic effects on AF. Methods We conducted electrophysiological studies in ibrutinib‐treated mice models to assess AF inducibility and the therapeutic efficacy of Wenxin Granules. Through network pharmacology screening, we identified potential molecular targets of Wenxin Granules. Subsequent proteomic analysis revealed specific targets through which Wenxin Granules may prevent ibrutinib‐associated AF. These targets were further validated in mice model experiments. Results Our study demonstrates that Wenxin Granules treatment in mice significantly reduces AF inducibility, shortens AF duration, and attenuates pathological cardiac remodeling, including left atrial (LA) enlargement and myocardial fibrosis ( p  < 0.05). Through comprehensive analysis integrating proteomics with network pharmacology‐predicted molecular targets, we systematically screened and identified 25 core therapeutic targets of Wenxin Granules, which are primarily associated with oxidative stress and calcium protein‐related signaling pathways. The ibrutinib treatment group demonstrated significantly elevated expression of reactive oxygen species (ROS)‐related proteins, including NOX2, NOX4, p22‐phox, and XO. Additionally, ibrutinib substantially increased the expression of ox‐CaMKII, p‐CaMKII (Thr‐286), and p‐RyR2 (Ser2814), resulting in enhanced abnormal sarcoplasmic reticulum (SR) Ca 2+ release, altered mitochondrial structures, and atrial fibrosis. Notably, Wenxin Granules administration reduced the expression of these proteins ( p  < 0.05). Conclusions These findings demonstrate that Wenxin Granules can ameliorate the occurrence and progression of AF induced by ibrutinib treatment, thereby laying the groundwork for further research and potential clinical applications in AF therapy.