Lipidomic and machine learning analysis reveals enantioselective mechanisms of hexaconazole-induced lipid metabolism disorder in 3T3-L1 preadipocytes

Lipid metabolism disorder is known to promote fat accumulation and increase the risk of metabolic syndrome. Hexaconazole (Hex) has been reported to disrupt lipid homeostasis while its mechanism of action and enantioselective behavior remain unclear. Therefore, this study investigated the effects of Hex enantiomers on lipid metabolism in 3T3-L1 preadipocytes. The results showed Hex induced lipid droplet accumulation, total Cholesterol (TC) content enhancement, along with the up-regulation of lipogenic genes and down-regulation of lipolytic genes in an enantioselective manner as (−)-Hex > Rac-Hex> (+)-Hex. Lipidomic analysis revealed the significant alterations in lipids of phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and ceramide (Cer) by Hex exposure leading to the interference of glycerophospholipid and sphingolipid metabolism. Machine learning suggested that (−)-Hex achieved the highest binding affinity with phosphatidic Acid Phosphatase (PLPP1) resulting in the activation of PLPP1-PA/DAG signaling pathway. This study elucidated the potential mechanism of lipid disruption by Hex, providing a theoretical basis for assessing the enantiomer-specific health risks of triazole pesticides.