Downregulation of PRDX3 promotes the progression of bradyarrhythmia via inducing ferroptosis and inflammatory macrophage infiltration in cardiac ganglion plexus

Aim Bradyarrhythmia is a prevalent cardiac disorder often necessitating lifelong pacemaker implantation, yet the underlying molecular mechanisms remain poorly defined. This study investigated the role of Peroxiredoxin 3 (PRDX3), a mitochondrial antioxidant enzyme, in the pathogenesis of bradyarrhythmia. Methods A rat model of bradyarrhythmia was constructed. In vivo telemetric ECG recording, transcriptome RNA-sequencing, flow cytometry, western blot, reverse transcription-quantitative PCR and enzyme-linked immunosorbent assay (ELISA) assay were performed to evaluate the potential function of PRDX3 in bradyarrhythmia. Results We observed a significant downregulation of PRDX3 in the cardiac ganglion plexus (CGP) in bradyarrhythmia rats. PRDX3 knockdown in primary CGP cells exhibited hallmark features of ferroptosis, including iron accumulation, lipid peroxidation and mitochondrial dysfunction. Mechanistically, PRDX3 deficiency led to excessive mitochondrial reactive oxygen species (ROS) accumulation, which inactivated the glutathione peroxidase 4 (GPX4) signaling pathway, thereby driving ferroptotic cell death. Restoration of PRDX3 expression in vivo significantly ameliorated bradyarrhythmia, and suppressed inflammatory cytokines production and M1 macrophage infiltration within the sinoatrial node. Furthermore, PRDX3 restoration alleviated ferroptosis and improved cardiac function by stabilizing heart rates and reducing R-R interval variability. Conclusion Our findings demonstrate that PRDX3 downregulation promotes bradyarrhythmia progression via inducing ferroptosis and inflammatory M1 macrophage infiltration, revealing a novel role of PRDX3 in bradyarrhythmia.