Berberine Reduces Atrial Lipotoxicity and Endoplasmic Reticulum Stress to Alleviate Heart Failure With Preserved Ejection Fraction ( <scp>HFpEF</scp> )‐Associated Atrial Fibrillation via <scp>AMPK</scp> Signaling

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently coexist due to shared risk factors, yet optimal therapeutic interventions remain elusive. Berberine (BBR), a widely used isoquinoline alkaloid, has demonstrated potential anti-arrhythmic properties. However, its specific effects and regulatory mechanisms in HFpEF-related AF are not fully understood. The present study was designed to clarify the pathological characteristics of HFpEF-associated AF and further evaluate the therapeutic effects of BBR. In this study, we developed a high-fat diet plus Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced murine HFpEF model to investigate the impact of berberine on the pathogenesis of HFpEF-associated AF. Bioinformatics and in vivo analyses revealed a progressive increase in atrial endoplasmic reticulum (ER) stress and lipid metabolic dysregulation. The HFpEF model exhibited significant atrial structural and electrical remodeling, which was dose-dependently reversed by berberine treatment. Further investigation showed that berberine effectively preserved atrial lipid metabolism, reduced ER stress and atrial inflammation, and restored atrial AMP-activated protein kinase (AMPK) activity. These protective effects were abolished by Compound C treatment, yet replicated by metformin or 4-phenylbutyric acid administration. Notably, the beneficial effects of berberine were validated in an isoprenaline/palmitic acid (ISO/PA)-treated HL-1 cell model. Our study highlights the therapeutic potential of berberine in mitigating HFpEF-associated atrial ER stress, lipid accumulation, and inflammatory responses. By targeting and preserving atrial AMPK signaling, berberine offers a promising therapeutic approach to combat HFpEF-associated AF.