Background: Plasticizers, including phthalate esters and phthalate-free alternatives, are widely detected environmental chemicals. Although increasing evidence suggests that plasticizers may disrupt gastrointestinal homeostasis, their potential molecular links with inflammatory gastrointestinal disorders (IGDs) remain unclear. Methods: This study aimed to systematically identify potential molecular targets and pathways linking representative plasticizers with IGDs. An integrative network toxicology framework was applied to investigate four plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), dioctyl phthalate/di(2-ethylhexyl) phthalate (DOP/DEHP), and acetyl tributyl citrate (ATBC), in relation to Crohn’s disease (CD), ulcerative colitis (UC), esophagitis, and gastritis. Plasticizer- and disease-related targets were collected from public databases, followed by overlapping target screening, protein–protein interaction network analysis, functional enrichment analysis, GEO-based transcriptomic validation, molecular docking, molecular dynamics simulation, and single-cell RNA-seq analysis. Results: Disease-specific candidate targets were identified, including CXCL8 and FN1 for CD, IL1B for UC, MAPK3, FASN, FN1, PPARG, CXCL8, FOS, and HIF1A for esophagitis, and MMP9, TNF, TLR4, IL6, CCR2, IFNG, and PTGS2 for gastritis. Cross-disease analysis further identified plasticizer-associated signature targets, including MMP7 for DMP, HMOX1 and NOS2 for DEP, and LTF and CCL11 for ATBC. Enrichment analysis indicated that these targets were mainly involved in inflammatory, chemokine, MAPK-related, and xenobiotic response pathways. Molecular docking and dynamics simulations suggested stable interactions between selected plasticizers and candidate targets, while single-cell analysis revealed their cell-type-specific expression patterns in epithelial, immune, and stromal compartments. Conclusions: This study provides an exploratory network toxicology framework for identifying potential molecular associations between plasticizer exposure and IGDs. The findings highlight disease-specific and plasticizer-associated candidate targets that may guide future experimental validation and environmental risk assessment.

Background: Ankylosing Spondylitis (AS) and inflammatory bowel disease (IBD) exhibit substantial pathophysiological overlap, including dysregulated innate immunity, barrier dysfunction, and Th17-mediated inflammation. However, whether Na⁺ overload-related genes (NRGs) exhibit shared transcriptional alterations in IBD and AS remains unclear. This study aimed to characterize the expression patterns of NRGs across IBD and AS and to identify candidate genes associated with both diseases. Methods: Differential expression analysis was performed to identify differentially expressed NRGs (DE-NRGs) in diseased tissues relative to normal tissues. Shared DE-NRGs between IBD and AS were screened and defined as common differentially expressed NRGs (Co-DE-NRGs). We then analyzed the correlations of these Co-DE-NRGs and explored their relationships with immune cell infiltration in target tissues. Four machine learning algorithms were applied to screen key NRGs associated with both IBD and AS. Potential therapeutic agents targeting these core biomarkers were predicted using drug–gene interaction databases, and molecular docking was conducted for further validation. Results: A total of 32 shared Co-DE-NRGs were identified for IBD and AS, with nine key regulatory NRGs recognized: CALR, CD63, CYBA, DYSF, HYOU1, IL1B, JAK1, MMP9, and STAT3. Exploratory MR analysis identified disease-specific associations between genetically predicted expression of NRGs and CD, UC, and AS. Genetically predicted STAT3 expression showed positive associations with CD and UC but an inverse association with AS and therefore did not represent a consistent risk factor across the three diseases. Furthermore, transcriptome-based drug-response analysis identified four candidate agents shared between AS and at least one IBD dataset: ciclosporin, BCL-LZH-4, BRD-K79669418, and CID-5951923. Exploratory molecular docking generated STAT3 binding poses for BCL-LZH-4 and CID-5951923, with DOCK Grid Scores of −35.321896 and −28.361128, respectively. CID-5951923 was selected for representative visualization of its predicted interaction with STAT3. Single-cell RNA-sequencing analysis identified tissue- and cell-type-specific STAT3 mRNA expression patterns in the analyzed IBD colonic and AS peripheral-blood datasets, with monocytes representing a major cell population exhibiting detected STAT3 expression in the AS dataset. Conclusions: These findings identify shared NRG-related transcriptional alterations in IBD and AS, with STAT3 emerging as a candidate gene associated with both diseases. Further experimental studies are required to determine whether these alterations reflect the involvement of NECSO and to evaluate their potential diagnostic or therapeutic relevance.