PON1 is a calcium-dependent HDL-associated enzyme with diverse catalytic activities that mediate protection against oxidative damage 1. Its primary function is hydrolyzing organophosphate insecticides and nerve gases, determining mammalian selective toxicity to these compounds 1. Additionally, PON1 displays lactonase activity—considered its native function—and arylesterase activity, enabling hydrolysis of oxidized lipids, lactones, and homocysteine thiolactone 23. Mechanistically, PON1 prevents low-density lipoprotein and cell membrane oxidation, contributing to HDL's antioxidative function and atheroprotective properties 4. It protects against systemic inflammation and oxidative stress; reduced PON1 activity is associated with dysfunctional HDL promoting atherosclerosis 4. PON1 additionally inhibits quorum sensing in gram-negative bacteria 4. Clinically, PON1 activity variations correlate with disease susceptibility. Genetic polymorphisms at positions 55 and 192 are major determinants of PON1 activity and influence atherosclerosis risk 1. Decreased plasma PON1 activity associates with sepsis severity and mortality 5, rheumatoid arthritis 6, Takayasu's arteritis 7, and panic disorder 8. These findings suggest PON1 activity measurement and genotyping may identify individuals at heightened risk for various inflammatory and oxidative stress-related conditions.