Carboxylesterase 2 as a potential molecular target for long-chain perfluoroalkyl carboxylic acids

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a broad and chemically diverse class of synthetic compounds widely used in industrial applications and consumer products. Human exposure to PFAS is widespread and occurs through multiple pathways, including drinking water, air, food, household dust, textiles, and cosmetics. PFAS have been linked to numerous adverse health effects and are a significant public health concern due to their extreme persistence in the environment, bioaccumulative properties, and broad biological activity. Despite growing evidence of PFAS toxicity, the molecular mechanisms underlying their biological effects remain incompletely understood, and the specific proteins involved have not been fully characterized. The aim of this study was to identify potential molecular targets for PFAS. Using protein target prediction tools, carboxylesterase 2 (CES2) was identified as a potential target for perfluoroalkylcarboxylic acids (PFCAs). These predictions were supported by molecular docking analyses. In vitro enzyme assays and experiments in HepG2 cells further support the potential inhibitory effects of PFCAs on carboxylesterase activity at micromolar concentrations. Furthermore, analysis of publicly available RNA-seq data from liver tissue of mice treated with PFCAs revealed overexpression of genes associated with Ces2a, the murine homologue of human CES2. These results suggest that PFCAs may contribute to adverse health effects, in part, through inhibition of CES2, a key enzyme involved in xenobiotic detoxification, drug metabolism, lipid metabolism, and energy homeostasis.