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Research Article: GPX7 marks fibroblast-associated stromal–innate immune crosstalk in ulcerative colitis

Date Published: 2026-05-22

Abstract:
Ulcerative colitis is sustained by stromal remodeling and innate immune activation. Whether serine-glycine-one-carbon metabolism contributes to fibroblast–macrophage crosstalk in ulcerative colitis remains unclear. We integrated two-sample Mendelian randomization, cross-cohort colonic transcriptomics, and single-cell RNA sequencing to prioritize serine-glycine-one-carbon–related candidates in ulcerative colitis, followed by qPCR validation in an infliximab-stratified cohort and a fibroblast–macrophage Transwell co-culture model. Signature-reversal analysis was used to nominate candidate modulators, whereas docking and molecular dynamics were applied as hypothesis-generating structural analyses. GPX7 emerged as the most consistently supported candidate, with concordant mucosal upregulation and orthogonal cis-pQTL support. GPX7-high mucosa was enriched for complement, chemokine, one-carbon metabolism, and extracellular matrix programs. Single-cell analyses localized GPX7 predominantly to a fibroblast state characterized by increased CXCL12 and MMP2 expression, strengthened intercellular communication, and elevated HIF1A activity, consistent with stromal–innate immune coupling. In an independent clinical cohort, GPX7 expression was higher in biopsies from infliximab non-responders than responders. In a fibroblast–macrophage Transwell system, co-culture amplified macrophage inflammatory transcripts and fibroblast remodeling-associated transcripts under LPS stimulation, and QL-X-138 attenuated these responses in an exploratory perturbation setting. Docking and molecular dynamics analyses provided preliminary structural plausibility for QL-X-138 as a candidate modulator of the GPX7-associated program. GPX7 marks a genetically supported fibroblast-associated stromal–innate immune crosstalk state in ulcerative colitis and supports further mechanistic investigation of stromal remodeling and innate inflammatory signaling.

Introduction:
Ulcerative colitis is sustained by stromal remodeling and innate immune activation. Whether serine-glycine-one-carbon metabolism contributes to fibroblast–macrophage crosstalk in ulcerative colitis remains unclear.

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