Abstract
Introduction: This study investigated the role of FCGR3A in pediatric inflammatory bowel disease (IBD) through integrated transcriptomic analysis and experimental validation, aiming to provide new mechanistic insights and therapeutic strategies. Methods: Transcriptomic datasets of pediatric IBD were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was applied to screen disease-related modules, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of overlapping DEGs. Hub genes were determined using protein-protein interaction networks, least absolute shrinkage and selection operator regression, and random forest algorithms. Their expression was verified by meta-analysis across multiple datasets, and diagnostic value was assessed using receiver operating characteristic (ROC) curves. The relationship between hub genes and immune infiltration was further explored. Functional assays included lipopolysaccharide (LPS)-stimulated intestinal epithelial and THP-1 macrophage models, as well as a dextran sulfate sodium (DSS)-induced murine colitis model. Results: WGCNA revealed 370 module genes associated with pediatric IBD, enriched in inflammatory pathways. Seven candidate genes were identified, among which FCGR3A showed a strong association with pediatric IBD. Immune infiltration analysis demonstrated that FCGR3A expression correlated with M1 macrophage enrichment. In vitro, FCGR3A was upregulated in LPS-induced epithelial cells, and its knockdown inhibited M1 macrophage polarization. In vivo, FCGR3A was highly expressed in DSS-induced murine colitis, promoting M1 polarization and disease progression. ROC analysis indicated strong predictive value (AUC = 0.968). Conclusion: FCGR3A may serve as a pivotal regulator in pediatric IBD by driving M1 macrophage polarization, representing a promising biomarker and potential therapeutic target.