GPX7标志着溃疡性结肠炎中成纤维细胞相关的基质先天免疫串扰
GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis.
摘要(中文译文)
溃疡性结肠炎由基质重塑和先天免疫激活所维持。丝氨酸-甘氨酸-一碳代谢是否参与溃疡性结肠炎中成纤维细胞与巨噬细胞的串扰尚不清楚。我们整合了双样本孟德尔随机化、跨队列结肠转录组学和单细胞RNA测序，以优先筛选溃疡性结肠炎中与丝氨酸-甘氨酸-一碳代谢相关的候选基因，随后在英夫利西单抗分层队列和成纤维细胞-巨噬细胞Transwell共培养模型中进行qPCR验证。采用特征逆转分析提名候选调节因子，而对接和分子动力学则作为产生假设的结构分析加以应用。GPX7成为获得最一致支持的候选基因，具有一致的黏膜上调表达和正交cis-pQTL支持。GPX7高表达黏膜富集补体、趋化因子、一碳代谢和细胞外基质相关程序。单细胞分析将GPX7主要定位于一种成纤维细胞状态，该状态以CXCL12和MMP2表达增加、细胞间通讯增强及HIF1A活性升高为特征，与基质-先天免疫耦联相一致。在一个独立临床队列中，英夫利西单抗无应答者活检组织中的GPX7表达高于应答者。在成纤维细胞-巨噬细胞Transwell系统中，LPS刺激下共培养放大了巨噬细胞炎症转录本和成纤维细胞重塑相关转录本，而QL-X-138在探索性扰动设置中减弱了这些反应。对接和分子动力学分析为QL-X-138作为GPX7相关程序的候选调节因子提供了初步的结构合理性。GPX7标记了溃疡性结肠炎中一种有遗传学支持的成纤维细胞相关基质-先天免疫串扰状态，并支持对基质重塑和先天炎症信号传导进行进一步的机制研究。
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.
如何引用
AMA
Jingui He, Rongrong Chen, Shaofan Qiu, Peimin Li, Xin Gao. GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1856998.
APA
Jingui He, Rongrong Chen, Shaofan Qiu, Peimin Li, Xin Gao (2026). GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1856998
GB/T 7714
Jingui He, Rongrong Chen, Shaofan Qiu, Peimin Li, Xin Gao. GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1856998.
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