Nutraceutical enhancement of paraoxonase 1 activity in chronic inflammation: A systematic review of animal-based and plant-based nutraceuticals

High-density lipoproteins (HDL-C) are traditionally viewed as cardioprotective due to their antioxidant capacity and role in cholesterol efflux. These properties are largely mediated by paraoxonase-1 (PON1), an enzyme embedded in the HDL-C membrane. Chronic inflammation, such as that sustained in rheumatoid arthritis (RA), can inactivate or displace PON1, converting HDL from anti-inflammatory to pro-inflammatory. This review aimed to identify nutraceutical compounds capable of enhancing PON1 activity and to evaluate their potential relevance to cardiovascular risk reduction in RA patients. A systematic PubMed search identified English-language randomized controlled trials (RCTs) published between 2010 and 2024 examining nutraceutical effects on PON1 or HDL function. Of 170 records screened, 23 RCTs met the inclusion criteria. Risk of bias was assessed using Cochrane methods. Nutraceuticals associated with improved PON1 activity included anthocyanins (10 RCTs, 80-320 mg/day), omega-3 fatty acids (4), chlorogenic acid (2), carotenoids such as lycopene and astaxanthin (2), epigallocatechin gallate (2), vitamin E (1), resveratrol (1), and berberine (1). Anthocyanins showed the most consistent benefit, with improvements in HDL-PON1 activity and cholesterol efflux capacity. Translation to diet is feasible; for example, one cup of blueberries provides ∼167 mg of anthocyanins. Lycopene reduced serum amyloid A-bound HDL in one trial, suggesting a mechanism to restore PON1 localization. Multiple nutraceuticals demonstrate potential to restore HDL's anti-inflammatory function via PON1 activation. However, nearly all evidence derives from non-RA populations. Rigorous RCTs in RA cohorts are needed to confirm efficacy, define dosing, and evaluate cardiovascular endpoints.