Abstract Body (Do not enter title and authors here): Introduction: Sinus node dysfunction (SND) induced by streptozotocin (STZ) is characterized by acute oxidative stress and chronic inflammatory damage, with hyperglycemia potentially contributing to the condition. While glucagon-like peptide-1 receptor agonists (GLP-1RA) exhibit cardiovascular benefits, their direct role in SND pathogenesis remains unexplored.

Hypothesis: We hypothesize that Supaglutide, a novel GLP-1RA, restores SAN function by activating the cAMP-PKA pathway, reducing oxidative stress, inflammation, and fibrosis, and reestablishing calcium homeostasis.

Methods: A streptozotocin (STZ)-induced SND rat model was evaluated at acute (7 days) and chronic (28 days) phases. Five groups were assigned: (1) Control, (2) Insulin, (3) Supaglutide, (4) Supaglutide + Exendin9-39 (acute), and (5) Supaglutide + Jant9-40 (chronic). Primary endpoints included electrophysiological parameters (HR, ADSNRT, IHR), SAN oxidative/molecular markers (ox-CaMKII/CaMKIIδ, SIRT3, p-RyR2/RyR2), and histology (fibrosis, apoptosis, CD86⁺macrophage infiltration).

Results:
Acute phase (7 Days):
- Supaglutide significantly improved heart rate, shortened ADSNRT, and increased intrinsic heart rate compared to control.
- These effects were abolished by GLP-1R antagonists (Exendin 9-39, Jant 9-40), confirming receptor dependence.
- Supaglutide reduced ox-CaMKII, elevated SIRT3 and p-RyR2 expression, and decreased apoptosis and CD86+ macrophage infiltration in SAN tissue.
- Insulin showed limited benefit.

Chronic phase (28 Days):
- Supaglutide sustained electrophysiological improvements, while significantly reducing collagen deposition.
- It decreased systemic TNF-α and IgG levels, improved hepatic and renal histopathology, and enhanced cardiac function.
- Insulin had modest effects and was significantly inferior to Supaglutide.
- Mechanistically, Supaglutide activated the GLP-1R/cAMP-PKA/CaMKII/SIRT3 signaling axis, offering a new strategy against oxidative and calcium clock dysfunction.

Conclusion: This study identifies Supaglutide as the first GLP-1RA capable of restoring SAN electrophysiology via oxidative and calcium signaling regulation, beyond glucose control. These findings not only uncover a novel function of GLP-1RA beyond metabolic regulation but also suggest that targeting SAN-specific mechanisms may represent a broader therapeutic strategy for arrhythmogenic cardiac diseases, especially those associated with metabolic disorders.