PON3 (paraoxonase 3) is a lactonase enzyme primarily synthesized in the liver and secreted into plasma, where it associates with high-density lipoproteins (HDLs) 1. Unlike PON1, PON3 lacks organophosphate-esterase activity but efficiently hydrolyzes lactones, including statin prodrugs and endogenous compounds 1. All paraoxonases, including PON3, exert potent antioxidant effects and are involved in cardiovascular disease pathology 1. PON3 is structurally associated with HDL particles, functioning as a calcium-dependent enzyme with reversible substrate binding 2. Recent proteomic and genetic studies identified PON3 as causally relevant for type 2 diabetes susceptibility, with shared genetic variants between PON3 and T2D risk 3. In heart failure, PON3 was among the most significantly down-regulated proteins in severely congested patients compared to non-congested controls, suggesting a protective role in cardiovascular homeostasis 4. Additionally, PON3 genetic alterations occur in salivary acinic cell carcinoma, where the PON3::LCN1 fusion was detected in ~22% of cases and associated with worse prognostic outcomes including metastasis and disease-related death 5. PON3 expression is regulated by DNA methylation patterns; differential methylation in the PON3 gene correlates with response to weight-loss interventions and serum protein levels 6. Intracellularly, PON3 modulates mitochondrial stress and may influence cancer cell survival 7.