Quercetin ameliorates doxorubicin-induced atrial fibrillation via EGFR-mediated restoration of autophagic flux

Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent associated with significant cardiotoxicity, particularly manifesting as atrial fibrillation (AF), which adversely impacts patient quality of life.

Purpose: This study aimed to investigate the effects of quercetin and its underlying mechanisms in doxorubicin (DOX)-induced AF.

Methods: Utilizing a mouse model, we compared DOX treatment with quercetin pre-treatment, examining the incidence and duration of AF, as well as the associated structural alterations in the atria, encompassing atrial enlargement, fibrotic changes, and oxidative stress.

Results: The findings from our study indicated that quercetin significantly alleviated DOX-induced AF by inhibiting phosphorylation of EGFR and TFEB, which consequently inhibited ATG5-mediated autophagosome formation and enhanced lysosomal degradation. Moreover, the use of an EGFR phosphorylation inhibitor, Nsc228155, reversed these effects at both cellular and murine levels. Furthermore, Knockdown of ATG5 by rAVV9-shATG5 strengthened the protective effects of quercetin on DOX-induce AF, whereas cardiac-specific overexpression of ATG5 by rAVV9-ATG5 partially abolished the protective effects of quercetin.

Conclusion: This work firstly reveals that quercetin prevents DOX-induced AF by targeting a novel EGFR/TFEB/ATG5-mediated autophagy-lysosomal axis, establishing it as the inaugural natural compound antagonizing chemotherapy-induced arrhythmia via phospho-EGFR inhibition. Our findings pioneer a therapeutic paradigm shifting from conventional antioxidant strategies toward precision Autophagy modulation, offering highly translatable cardioprotection for Cancer patients with immediate clinical potential.

Atrial fibrilliation; Autophagy; Doxorubicin; Oxidative stress; Quercetin.