DINCH induces intestinal toxicity through "ROS-ENO1-PA-lipid peroxidation" axis: An integrated approach combining network toxicology and experimental validation
Abstract
Cyclohexane-1,2-dicarboxylic acid diisononyl ester (DINCH), as a "green" alternative to phthalates, has been widely used in consumer products and industrial materials. Consequently, its environmental and human exposure levels continue to rise, necessitating a systematic evaluation of its mechanism of intestinal toxicity. This study developed a strategy integrating "network toxicology-machine learning-molecular simulation-experimental validation": First, multiple databases were combined to identify potential intestinal toxicity targets of DINCH, followed by the construction of a PPI network and the identification of the core pathway "metabolic pathway" through GO/KEGG enrichment. Subsequently, ENO1 was selected by machine learning. Molecular docking and molecular dynamics simulations consistently demonstrate a interaction between DINCH and ENO1. In vitro experiments confirmed that high concentrations of DINCH significantly downregulated ENO1 expression and attenuated the H₂O₂-induced increase in ENO1 levels, leading to ROS accumulation, mitochondrial dysfunction, and lipid peroxidation. Furthermore, experiments with ENO1 gene silencing demonstrated that DINCH-induced lipid peroxidation was dependent on ENO1. Exogenous supplementation of PA significantly reversed DINCH-triggered mitochondrial damage, and lipid peroxidation. NAC and Mito-TEMPO interventions also alleviated the H₂O₂ + DINCH-induced lipid peroxidation. In summary, this study is the first to elucidate the novel…
Read the paper
Related studies
- Combining in silico and in vitro approaches to identification of potent inhibitor against phospholipase A2 (PLA2)
- In silico and in vitro studies: investigating the chemical composition, DFT, molecular docking, and dynamic simulation of Satureja candidissima (Munby) Briq essential oil as a potential antibacterial agent
- Quercetin combined with ciprofloxacin and gentamicin inhibits biofilm formation and virulence in Staphylococcus aureus
- In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs
- Anticonvulsant Effects of Citronellal, Daidzin, and Phytol, Possibly Through GABAA Receptor and Voltage-Gated Sodium Channel Interaction Pathways: In Vivo and In Silico Studies
- 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as D3R-Selective Ligands for 3D-QSAR, Docking and Molecular Dynamics Simulation Studies
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.