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Abbreviations AC: Adenylyl cyclase Akt: Protein kinase B BP: Blood pressure cAMP: Cyclic adenosine monophosphate CDK2: Cyclin-dependent protein kinase 2 CVD: Cardiovascular disease DBP: Diastolic blood pressure DM: Diabetes mellitus EGFR: Epidermal growth factor receptor Epac: Exchange protein directly activated by cAMP ER: Endoplasmic reticulum Ex-4: Exendin-4 GLP-1: Glucagon-like peptide-1 GLP-1 RAs: GLP-1 receptor agonists GLUT1: Glucose transporter 1 HF: Heart failure HFpEF: Heart failure with preserved ejection fraction HFrEF: Heart failure with reduced ejection fraction H/R: Hypoxia/reoxygenation I/R: Ischemia/reperfusion LV: Left ventricular MACE: Major adverse cardiovascular events MAPK: RAS/RAF/MEK1/2/ERK1/2 NLRP3: Nod-like receptor thermal protein domain associated protein 3 PAH: Pulmonary arterial hypertension PCI: Percutaneous coronary intervention PI 3 K: Phosphatidylinositol 3-kinase PKA: Protein kinase A SBP: Systolic blood pressure STEMI: ST-segment elevation myocardial infarction VSMCs: Vascular smooth muscle cells References Senior PA

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Taken together, these findings suggest that NSBSO-induced GSH depletion and synthesis inhibition can elevate intracellular ROS, thereby activating the caspase family, leading to GSDME cleavage and cell pyroptosis

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