GART expression correlates with proliferative and purine-metabolic states in ulcerative colitis tissueGART Expression Linked to Specific Cell States in Ulcerative Colitis

To characterize the epithelial state associated with GART expression in ulcerative colitis (UC) and determine whether this association reflects a GART-specific program or a broader proliferative and purine-metabolic phenotype. Four independent bulk transcriptomic cohorts were analyzed and synthesized by random-effects meta-analysis. Human colonic scRNA-seq datasets (GSE214695 and SCP259) were integrated, with principal comparisons repeated using donor-aware pseudobulk or mixed-effects approaches and adjustment for sequencing depth, gene detection, and cell-cycle covariates. GART detection was defined from raw counts and tested using alternative thresholds. Pseudotime, scTenifoldKnk, CellChat/LIANA, and transcriptional-network analyses were used as exploratory analyses. Spatial transcriptomics (GSE189184), human colonic multiplex immunofluorescence, and acute DSS-induced colitis tissues were used for tissue-level localization. Across the four bulk cohorts, GART expression showed an overall increase in UC (pooled Hedges’ g = 0.743, 95% CI 0.239–1.248; P = 0.0183). In the single-cell atlas, GART detection localized preferentially to an ISC-like epithelial compartment, although the magnitude of the UC-associated detection difference varied between cohorts. Within UC ISC-like cells, donor-paired pseudobulk analyses identified proliferative and nucleotide-metabolic transcriptional differences associated with GART detection. Across the broader ISC-like epithelial atlas, donor-aware module analyses showed positive associations of GART detection with purine-biosynthesis, DNA-replication, DNA-repair, and mitotic programs, and these associations remained positive within cell-cycle strata. Comparison with other de novo purine-synthesis enzymes did not support a uniquely GART-specific alteration. Exploratory network analyses linked the GART-associated state to proliferative and nucleotide-metabolic programs but did not establish functional dependence. In seven independent spatial donors, the single-cell-derived epithelial program was consistently higher in GART-detected than GART-undetected epithelial regions (mean within-donor difference = 0.0262, 95% CI 0.0140–0.0407; exact P = 0.0156). Human tissue immunofluorescence further showed co-enrichment of GART with OLFM4-positive ISC-like, MYBL2/Ki67-positive proliferative, and MIF/CD74-associated inflammatory regions across the corresponding panel-specific participant sets. GART identifies a proliferative and purine-metabolic ISC-like epithelial state in UC but is not established as a specific driver of epithelial regeneration. The findings support an association between GART detection, nucleotide-demand programs, proliferative epithelial activity, and the inflammatory tissue context, providing a framework for future direct functional studies.