Acetyl tributyl citrate (ATBC) and epoxidized soybean oil (ESBO) are widely used emerging plasticizers, but their potential to induce lipid metabolism disorders remains poorly understood. In this study, we explored their toxicological mechanisms using a network toxicology framework combined with molecular docking and molecular dynamics simulations. Potential targets of ATBC and ESBO were predicted from multiple databases and compared with genes associated with lipid metabolism disorders. Core targets were identified through protein-protein interaction network analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analyses were performed to infer relevant biological processes and pathways. Molecular docking and dynamics simulations were further applied to evaluate the binding affinity and stability between the compounds and key targets. Five core targets -- epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), toll-like receptor 4 (TLR4), JUN proto-oncogene (JUN), and androgen receptor (AR) -- were identified, mainly involved in immune regulation, hormone signaling, and the hypoxia-inducible factor 1 (HIF-1) pathway. Enrichment analyses suggested that the emerging plasticizers ATBC and ESBO may disturb lipid metabolism and contribute to diseases such as non-alcoholic fatty liver disease (NAFLD) and hormone-sensitive cancers. Docking results confirmed strong and specific interactions between the compounds and core targets. Overall, these findings support the hypothesis that ATBC and ESBO may disrupt hepatic lipid metabolism through HIF-1 activation and immune-endocrine pathway interference, providing insight into their potential health risks.

In recent years, the impact of environmental pollutants on lipid metabolism has attracted widespread attention. These pollutants can interfere with lipid synthesis, storage, and oxidation through various signaling pathways, ultimately leading to metabolic disorders. Plasticizers, widely used in food packaging, medical devices, children's toys, and construction materials, have become common environmental contaminants. Among them, phthalate esters (PAEs) are extensively applied due to their excellent plasticizing properties. However, studies have indicated potential health risks associated with PAEs, particularly concerning their role in lipid metabolism regulation.

For example, diisobutyl phthalate exhibits high-affinity binding to peroxisome proliferator-activated receptor gamma (PPARγ) and modulates lipid homeostasis via phospholipase D and phosphoinositide 3-kinase/protein kinase B signaling pathways. Di(2-ethylhexyl) phthalate (DEHP) promotes lipid synthesis through the liver X receptor/sterol regulatory element-binding protein-1c pathway while inhibiting the calcium/calmodulin-dependent protein kinase beta/AMP-activated protein kinase pathway, thereby reducing fatty acid oxidation. Furthermore, dibutyl phthalate (DBP) may induce inflammation by disrupting the gut-liver axis, while diethylene glycol dibenzoate exhibits a non-monotonic dose-dependent effect, potentially increasing the risk of obesity.

Due to the toxicity concerns associated with traditional plasticizers, regions such as the European Union and the United States have gradually restricted their use in food-contact materials and children's products, driving the search for low-toxicity and high-efficiency alternatives. Epoxidized soybean oil (ESBO) and acetyl tributyl citrate (ATBC) have been proposed as potential safer alternatives due to their perceived "green" and environmentally friendly properties. ESBO demonstrates excellent thermal stability and relatively low toxicity, making it widely used in food packaging and medical devices. Meanwhile, ATBC, known for its biocompatibility, is frequently employed in cosmetics and children's toys. However, with the exponential increase in their usage, the environmental release and biological exposure risks of emerging plasticizers have become increasingly evident.

ATBC, in particular, lacks strong covalent bonding with polymeric materials, making it prone to environmental leaching and subsequent bioaccumulation. Its maximum migration level has been reported to reach 79.8 mg/kg, surpassing that of some PAEs. Moreover, both ATBC and ESBO have been widely detected in aquatic environments, soil, airborne particulates, and human biological samples, suggesting widespread population exposure and potential metabolic disruptions. ATBC may interfere with lipid homeostasis by regulating cholesterol metabolism and lipoprotein levels, while also affecting thyroid hormone synthesis and secretion -- critical regulators of energy metabolism and lipid homeostasis. As an epoxide, ESBO undergoes hydrolysis in vivo, generating biologically active metabolites that may modulate hepatic metabolic enzyme activity, influencing lipid transport and storage, and ultimately contributing to metabolic imbalances. Although short-term toxicity studies suggest that ATBC and ESBO exhibit relatively low acute toxicity, their long-term effects on lipid metabolism and underlying molecular mechanisms remain poorly understood.

Current research on plasticizer-induced lipid metabolism disorders has predominantly focused on traditional PAEs, with systematic studies on emerging alternatives still lagging. Existing evidence suggests that emerging plasticizers may disrupt metabolic homeostasis through mechanisms similar to those of PAEs. For instance, ATBC has been proposed to interfere with estrogen, androgen, and thyroid hormone signaling pathways, thereby influencing lipid metabolism, energy balance, and cholesterol biosynthesis. However, conventional toxicological approaches often fail to capture the complex, multi-target, and multi-pathway interactions that occur under real-world exposure conditions.

Network toxicology, an emerging research paradigm, integrates bioinformatics and systems biology to holistically elucidate the potential targets and toxicological pathways of chemical exposures. This approach offers a novel perspective for systematically assessing the health risks associated with environmental pollutants. This study focuses on ATBC and ESBO, two representative emerging plasticizers, aiming to systematically predict their potential targets using network toxicology and validate their binding affinities to key lipid metabolism-related proteins through molecular docking techniques. By constructing a comprehensive "compound-target-pathway" interaction network, this study seeks to elucidate the core mechanisms by which these plasticizers interfere with lipid synthesis, degradation, and transport. The findings will provide a theoretical basis for assessing the health risks of emerging plasticizers, contribute to the development of low-toxicity alternatives, and support the formulation of targeted intervention strategies. This research holds significant scientific value for safeguarding public health and promoting the sustainable application of alternative materials.