GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis

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.