Comprehensive utilization of in silico approach and in vitro experiment to unveil the molecular mechanisms of mono (2-ethylhexyl) phthalate-induced lung adenocarcinoma

Mono (2-ethylhexyl) phthalate (MEHP), the main bioactive metabolite of commonly used plasticizer Di (2-ethylhexyl) phthalate, has received increasing attention due to its carcinogenic toxicity. This study aims to systematically explore the molecular mechanisms underlying MEHP-induced lung adenocarcinoma (LUAD). Firstly, network toxicology was employed to construct the interaction network of MEHP-targeted LUAD-related proteins and identify core proteins. Subsequently, functional analyses were used to determine the key pathways of these proteins enriched. Next, expression and survival analyses of multiple public datasets were conducted to emphasize the importance of core genes, and an optimized prognostic model was constructed based on independent prognostic genes to explore the relationship of gene risk with immune infiltration and immunotherapy. Ultimately, molecular docking and dynamics simulation were used to predict the binding modes and affinities of MEHP with core proteins, and surface plasmon resonance experiments were utilized to further validate their direct interactions. The findings demonstrated that MEHP targets 167 LUAD-related proteins, including 28 core target proteins. These proteins form the critical networks that regulate Cancer and immune-associated pathways to induce the occurrence and development of LUAD, and further coordinate patient prognosis and treatment by altering the immune microenvironment. Most importantly, their direct interactions (especially PTGS2) lay the structural foundation of MEHP regulating core proteins, greatly supporting its LUAD toxicity. In conclusion, this study introduces a novel approach for evaluating the safety of plasticizers and elucidates the molecular mechanisms behind MEHP-induced LUAD, thus offering new and effective targets and strategies for Cancer prevention and treatment.

Lung adenocarcinoma toxicity; Molecular docking; Molecular dynamics simulation; Mono (2-ethylhexyl) phthalate; Network toxicology; Surface plasmon resonance.