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Background 5-Aminosalicylic acid (5-ASA) remains the first-line therapy for mild-to-moderate ulcerative colitis (UC). However, only half of the patients exhibit a good response. The mechanisms underlying inter-individual variation in 5-ASA efficacy remain unclear. This study integrated plasma proteomics with mechanistic validation to elucidate the role and underlying mechanisms of sulfotransferase family 1A member 1 (ST1A1, gene name SULT1A1) in modulating 5-ASA therapeutic efficacy.Methods Baseline serum from 36 UC patients (18 responders and 18 non-responders after 5-ASA treatment) were analyzed using Olink proteomics, and verified by ELISA, immunohistochemistry, and western blot. Functional studies were performed in NCM460 cells through siRNA-mediated knockdown or plasmid overexpression and the stimulation with dextran sulfate sodium (DSS) or lipopolysaccharide (LPS). Intracellular 5-ASA was quantified by high-performance liquid chromatography. Transcriptome sequencing and GSVA analysis identified differentially enriched pathways. ST1A1-targeted adeno-associated virus (AAV) intestinal epithelial Sult1a1-knockdown mouse model was established to assess ST1A1 function in vivo.Results Olink proteomic profiling identified ST1A1 as significantly elevated in 5-ASA-ineffective patients ( IDDF2026-ABS-0182 Figure 1(A)), which was subsequently confirmed by its upregulation in plasma and colonic mucosa in an independent validation cohort (IDDF2026-ABS-0182 Figure 1(B-D)). In vitro, SULT1A1 knockdown could ameliorate both DSS- and LPS-induced inflammatory cytokine expression and the destruction of tight junction proteins, whereas overexpression had the opposite effects. Mechanistically, ST1A1 activated the EGFR-MAPK axis, suppressed 5-ASA epithelial uptake transporter organic anion transporting polypeptide 1B3, and induced 5-ASA metabolic enzyme N-acetyltransferase 1, thereby reducing intracellular 5-ASA level. In vivo, Sult1a1 knockdown alleviated mouse DSS colitis, increased the colonic levels of 5-ASA and thus enhanced the anti-inflammatory effect of 5-ASA (IDDF2026-ABS-0182 Figure 1(E-I)).Conclusions ST1A1 promotes intestinal inflammation and contributes to 5-ASA resistance by activating the EGFR-MAPK pathway, reducing 5-ASA uptake, and increasing its metabolism. Targeting ST1A1 may enhance therapeutic efficacy and enable biomarker-guided precision therapy in UC.Abstract IDDF2026-ABS-0182 Figure 1