Integrative Computational Food Toxicology Implicates a CXCL1-Associated Fibroblast Inflammatory Remodeling Signature...

Deoxynivalenol (DON) is a prevalent trichothecene mycotoxin with well-recognized intestinal toxicity, yet the molecular and cellular remodeling patterns associated with DON-related intestinal barrier dysfunction remain incompletely understood. Here, an integrative computational framework combining network toxicology, bulk transcriptomics, WGCNA, machine learning, immune infiltration analysis, molecular docking, single-cell transcriptomics, CellChat, and in silico gene perturbation was applied. A total of 1119 distinct genes were obtained from the traceable retained intestinal disease- and barrier-related lists from CTD, GeneCards, OMIM, and PharmGKB. Intersecting this set with differentially expressed genes and genes in the disease-associated WGCNA module yielded 23 database- and transcriptome-supported intestinal disease/barrier candidate genes, which were subsequently evaluated for their potential relevance to DON-related intestinal barrier dysfunction. Machine learning further prioritized six hub genes: SLC6A14, TIMP1, CXCL1, S100A11, LCN2, and NOS2. Single-cell mapping highlighted fibroblasts as an important disease-associated stromal compartment, while CellChat analysis revealed enhanced CXCL signaling in disease samples. CXCL1 showed prominent expression in disease-associated fibroblasts, and its in silico knockout perturbed genes related to inflammatory remodeling, oxidative stress, extracellular matrix organization, and stromal activation. Fibroblast subclustering further identified disease-enriched CXCL-associated inflammatory and stress-response states. Overall, these findings identify CXCL1-associated fibroblast inflammatory remodeling as a candidate stromal context potentially relevant to DON-related intestinal barrier dysfunction, rather than as a DON-specific mechanism, and provide a hypothesis-generating basis for future experimental validation.