Background: Atrial fibrillation (AF) is the most prevalent sustained arrhythmia, whose clinical management faces numerous challenges, including high recurrence rates and significant adverse effects associated with current therapies. Myricetin, a natural flavonoid compound, has shown unique therapeutic potential due to its multitarget cardioprotective properties and favorable safety profile. This study aimed to elucidate the specific molecular mechanisms through which myricetin mitigates AF.

Methods: Human atrial fibroblasts (hAFs) were transfected with or without short hairpin RNA (shRNA) targeting estrogen receptor 1 (ESR1) and subsequently exposed to various concentrations of myricetin and/or angiotensin II (Ang II). To examine the involvement of autophagy and oxidative stress, specific groups were treated with the autophagy inhibitor 3-methyladenine (3-MA) and the antioxidant N-acetyl cysteine (NAC). Then efficacy evaluation was performed employing 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays for cell viability, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, flow cytometry, and co-immunoprecipitation (Co-IP) analyses.

Results: Myricetin effectively reversed Ang II-induced reductions in cell viability and increases in apoptosis (p < 0.05). It significantly stabilized ESR1 by attenuating reactive oxygen species (ROS)-dependent ubiquitination (p < 0.001), leading to marked decreases in endoplasmic reticulum (ER) stress markers (glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein (CHOP)), as well as autophagy indicators (Beclin and microtubule-associated proteins 1A/1B light chain 3B (LC3II/LC3I)) (p < 0.01).

Conclusion: Myricetin emerges as a promising therapeutic candidate for AF management by reducing ESR1 ubiquitination and suppressing ER stress-related autophagy, thereby enhancing cellular resistance to stress-induced injury. These findings suggest that myricetin could be incorporated into existing AF therapeutic strategies to improve efficacy and safety outcomes.