Paraoxonases as metabolic and signaling modulators: prospects for therapeutic and preventive implications.

Paraoxonases (PONs) are a family of three isozymes, PON1, PON2, and PON3, with lactonase and esterase enzymatic activities. These enzymes have been implicated in the pathophysiology of numerous disorders, including cancer, atherosclerosis, liver diseases, neurodegenerative conditions, and toxicities. Specifically, alterations in PONs, such as changes in gene expression, mRNA levels, protein abundance, and enzymatic activity, have been associated with a range of pathological conditions. PONs are primarily linked to these disorders through their antioxidant and detoxifying functions, although additional, yet unidentified, mechanisms may also contribute. A growing body of evidence indicates that modulating PON levels or activity of PONs may confer therapeutic benefit in the prevention, management, and treatment of certain diseases. Promising strategies include enzyme replacement therapy, drug repurposing, and genetic engineering techniques aimed at restoring or enhancing PON function. Moreover, PONs' level and activity can be influenced by life-style factors and the microbiome, offering additional avenues for intervention. In this review, we propose that the modulation of PONs holds therapeutic and preventive potential, and we discuss the current and emerging strategies by which this may be achieved.