{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:25:33Z","timestamp":1787246733843,"version":"build-2736575974"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Resistance to anti-TNF\u03b1 therapy (e.g., infliximab) in ulcerative colitis (UC) remains a significant clinical challenge, with the underlying cellular and spatial mechanisms poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study establishes fibroblast-derived IGFBP5 as a central mediator of anti-TNF\u03b1 resistance in UC. The IGFBP5-EGR1-VEGFR2 axis may represent a candidate predictive biomarker and a promising target for overcoming treatment resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1841149","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:34:56Z","timestamp":1787243696000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics analysis identifies fibroblast IGFBP5 as a key target of anti-TNF\u03b1 therapy in ulcerative colitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Peihong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]},{"name":"School of Biological Sciences, Nanyang Technological University","place":["Singapore, 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