RYR2 encodes the cardiac ryanodine receptor, a sarcoplasmic reticulum calcium-release channel essential for excitation-contraction coupling in cardiac muscle 1. The channel mediates calcium efflux from the sarcoplasmic reticulum into the cytosol, triggered by L-type calcium channel activation, thereby initiating cardiac contraction 2. RYR2 also regulates intracellular calcium homeostasis and is required for embryonic heart development. RYR2 dysfunction arises through two distinct mechanisms. Gain-of-function mutations cause excessive spontaneous calcium release, leading to catecholaminergic polymorphic ventricular tachycardia (CPVT), the most common RYR2-related arrhythmia, characterized by stress-induced polymorphic ventricular tachycardia and sudden cardiac death risk 13. Loss-of-function variants cause calcium release deficiency syndrome (CRDS) with impaired calcium release 1. Additionally, pathological post-translational modifications—phosphorylation and oxidation—destabilize the closed channel state, causing pathological diastolic calcium leak associated with heart failure and atrial fibrillation 2. Current CPVT management includes β-blockers and flecainide, with emerging therapeutic strategies targeting calcium handling through phosphodiesterase gene therapy and RYR2-stabilizing drugs (rycals) 23. Recent evidence demonstrates that suppressing aberrant RYR2 phosphorylation via STAT3/CaMKII inhibition prevents postoperative atrial fibrillation 4. Understanding RYR2 pathophysiology is critical for personalized treatment of diverse cardiac arrhythmias.