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

ABSTRACT 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.