Liao_2025_Toxicol.Appl.Pharmacol__117454

Carbamate pesticides (CMs), which are widely applied in agricultural production and living environments, have been confirmed to exhibit disruptive effects on lipid metabolism as environmental endocrine disruptors. The present study aims to investigate the inhibition behavior of CMs on the activity of the critical hydrolytic enzymes, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2), to elucidate the toxicity mechanisms from a novel perspective. Based on network toxicology analysis, CESs were identified as potential targets for CMs-induced lipid metabolism disorders. In vitro incubation experiments demonstrated that most CMs strongly inhibited the activity of CES1 and CES2, with inhibition ratios exceeding 80 %. Kinetic studies and in vitro-in vivo extrapolation revealed that CMs might disrupt the metabolic homeostasis of lipids by inhibiting CESs in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of CMs towards CESs. Cellular fluorescence imaging confirmed the inhibition of CMs on CESs in HepG2 cells. These findings provide new experimental evidence for understanding the mechanism of CMs-mediated lipid metabolism disorders through inhibition on CESs.