Shared inflammatory targets of phthalate plasticizers in MODS-related syndromes: An integrative network toxicology study with representative DEHP in vitro validation

Phthalate esters (PAEs) are widely used in medical-grade polyvinyl chloride Materials and may contribute to inflammatory injury under medical-device-relevant exposure conditions. However, the shared molecular targets linking different phthalates to multiple organ dysfunction syndrome (MODS)-related pathological processes remain unclear. Here, an integrative network toxicology approach was used to identify shared candidate inflammatory targets of diethyl phthalate (DEP), dimethyl phthalate (DMP), and dioctyl phthalate (DOP) within a MODS framework, with focused analyses of three clinically relevant MODS-related syndromes: sepsis, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS). Compound- and disease-associated targets were integrated to construct interaction networks, identify hub genes, and perform pathway enrichment and molecular docking analyses. To provide representative experimental support, di- (2-ethylhexyl) phthalate (DEHP) was selected for in vitro validation in A549, HK-2, and RAW264.7 cells. Network analysis identified recurrent candidate inflammation-related targets, with STAT3, PTGS2, and TLR4 repeatedly prioritized across the MODS-related syndrome analyses. Acute 24 h DOP/DEHP exposure reduced cell viability, increased Apoptosis, elevated IL-6, TNF-α, IL-1β, and IL-18 secretion, and was associated with increased expression of TLR4, STAT3, and PTGS2 in all three cell models. These findings identify shared candidate inflammatory targets networks of representative phthalate plasticizers in MODS-related syndromes and provide hypothesis-generating evidence supporting conserved inflammatory responses to representative DOP/DEHP exposure.