Divaroside alleviates barium chloride-induced arrhythmia by activating the Nrf2/HO-1 axis to modulate autophagy and calcium homeostasis

Background Acanthopanax sessiliflorus ( A. sessiliflorus ) extract has been used in various traditional Chinese medicines and compound preparations for the treatment of arrhythmia. Our preliminary studies have demonstrated that A. sessiliflorus extract exerts significant protective effects against arrhythmia induced by barium chloride. The present study aims to elucidate the bioactive components of A. sessiliflorus and to investigate the underlying mechanisms by which it mitigates barium chloride-induced arrhythmia. Methods Network pharmacology was employed to predict the pharmacological profiles of chemical constituents from A. sessiliflorus, followed by a systematic screening of their biological activities. Subsequently, a barium chloride-induced arrhythmia model was established, and the potential therapeutic mechanisms were analyzed using transcriptomics. Functional and histopathological analyses of the rat hearts were performed. Western blot was used to detect the expression levels of the Nrf2/HO-1 axis, connexins, ion channels, and autophagy-related proteins in myocardial tissue and NRVMs. Subsequently, PCR, immunofluorescence, co-immunoprecipitation, and molecular docking were employed to verify the involvement of the targets in the intervention of arrhythmia. Results The results showed that after treatment with divaroside, the arrhythmia and redox system imbalance induced by BaCl₂ in rats were significantly restored. Divaroside can inhibit calcium overload by regulating the expression levels of RyR2 and SERCA2a in the sarcoplasmic reticulum, serving as a means to alleviate arrhythmia. In addition, we have confirmed that autophagy plays a crucial role in arrhythmia, and divaroside can activate autophagy, thereby protecting cardiomyocytes from BaCl₂-induced damage. Finally, it was confirmed that divaroside can weaken the interaction between the Keap1-Nrf2 complex and promote the nuclear translocation of Nrf2, activating the Nrf2/HO-1 axis and regulating the aforementioned pathways to counteract arrhythmia. Conclusion This study suggests that divaroside prevents the occurrence of arrhythmia by activating autophagy and reducing abnormal calcium ion homeostasis through the Nrf2/HO-1 axis.