Multi-omics analysis identifies fibroblast IGFBP5 as a key target of anti-TNFα therapy in ulcerative colitis.

BACKGROUND: Resistance to anti-TNFα therapy (e.g., infliximab) in ulcerative colitis (UC) remains a significant clinical challenge, with the underlying cellular and spatial mechanisms poorly understood. METHODS: We integrated bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) from clinical cohorts to systematically map the cellular landscape and identify key determinants of treatment response, followed by validation in independent clinical cohorts and in vitro functional experiments. RESULTS: Multi-omics cross-analysis pinpointed insulin-like growth factor-binding protein 5 (IGFBP5) as a fibroblast-specific, spatially enriched gene strongly associated with infliximab non-response. Functional analyses linked IGFBP5 to inflammatory pathways and a distinct immune-activated microenvironment. Cell-cell communication analysis revealed that IGFBP5-high fibroblasts exhibit enhanced crosstalk with monocytes, endothelial cells, and T cells via VEGF, MIF, and WNT signaling. Validation in clinical samples and functional experiments confirmed elevated expression of IGFBP5 and its downstream effectors EGR1 and VEGFR2 in non-responders, Mechanistically, IGFBP5 promoted activation of the VEGFR2/EGR1 signaling axis and enhanced the secretion of inflammatory mediators, including IL-6, CXCL12, and CCL2, thereby contributing to a pro-inflammatory fibroblast phenotype. CONCLUSIONS: This study establishes fibroblast-derived IGFBP5 as a central mediator of anti-TNFα resistance in UC. The IGFBP5-EGR1-VEGFR2 axis may represent a candidate predictive biomarker and a promising target for overcoming treatment resistance.