Matrine Inhibits the Wnt3a/β‐Catenin Signalling to Attenuate Pressure Overload‐Induced Atrial Remodelling and Vulnerability to Atrial Fibrillation

Atrial fibrillation (AF) is closely associated with atrial electrical and structural remodelling, yet effective drug strategies remain limited. Matrine (MAT), the active compound in Sophora flavescens, has shown anti-AF effects, but its mechanisms are unclear. This study explored MAT's impact on pressure overload-induced AF using clinical samples, bioinformatics, network pharmacology and murine models, focusing on the canonical Wnt signalling. A murine pressure overload model was established via transverse aortic constriction (TAC) surgery for 4 weeks. Programmed electrical stimulation, langendorff perfusion, echocardiography, Masson's trichrome staining and western blotting were used to evaluate the potential effects and mechanisms of MAT. The results demonstrated that TAC-induced atrial electrical and structural remodelling significantly increased susceptibility to AF in mice while also up-regulated atrial Wnt3a/β-catenin signalling as well as markers for remodelling and inflammation, which were partially supported by clinical samples. MAT dose-dependently mitigated atrial structural and electrical remodelling. Furthermore, MAT intervention inhibited Wnt3a/β-catenin signalling. However, co-administration of SKL2001, a Wnt/β-catenin agonist, counteracted MAT's benefits. The overall findings suggest that MAT treatment may serve as a potential therapeutic approach for inhibiting TAC-induced atrial electrical and structural remodelling by suppressing Wnt3a/β-catenin signalling pathways, thereby reducing susceptibility to AF.