circPLCE1 Loss Drives Fibrosis in Crohn’s Disease : Gut | May 2026

Introduction

Intestinal fibrosis is a major complication of Crohn’s Disease and remains a leading cause of bowel strictures, obstruction and repeated surgery. Current anti-inflammatory therapies have limited efficacy once fibrotic remodeling becomes established, highlighting the urgent need for mechanistic antifibrotic targets. Emerging evidence suggests that fibroblast metabolic reprogramming is central to organ fibrosis, although its contribution to intestinal fibrogenesis in Crohn’s disease has remained incompletely understood.

Problem Statement

The metabolic pathways that sustain activated intestinal fibroblasts and extracellular matrix deposition in Crohn’s disease are poorly characterized. In particular, the role of the Pentose phosphate pathway and its upstream regulatory networks in intestinal fibrosis has not previously been defined.

Summary

Using integrated metabolomics, single-cell RNA sequencing and spatial transcriptomics from paired strictured and non-strictured intestinal tissue, this study identified marked activation of the pentose phosphate pathway (PPP) within intestinal fibroblasts during Crohn’s-associated fibrosis. The investigators demonstrated that xylulokinase (XYLB)-mediated generation of xylulose-5-phosphate promoted extracellular matrix synthesis through epigenetic enhancement of collagen transcription. This established PPP activation as a direct driver of fibroblast profibrotic activity rather than merely a metabolic bystander phenomenon.

Mechanistically, the study identified downregulation of the circular RNA circPLCE1 as a central upstream regulator of this metabolic reprogramming. Reduced circPLCE1 expression enhanced PPP activation, increased glycolytic flux and elevated nicotinamide adenine dinucleotide phosphate production, collectively promoting fibroblast activation and intestinal fibrosis both in vitro and in murine fibrosis models. Importantly, circPLCE1 directly interacted with the catalytic domain of XYLB, competitively inhibiting its enzymatic activity. Loss of circPLCE1 therefore restored XYLB function and led to accumulation of xylulose-5-phosphate, driving sustained fibrogenic signaling.

Fibroblast-specific circPLCE1 knockdown in vivo significantly aggravated intestinal fibrosis, confirming the biological importance of this regulatory axis. The study further linked metabolic rewiring to epigenetic collagen regulation, reinforcing the emerging concept that immunometabolic pathways are central to chronic fibrostenotic disease progression in Crohn’s disease.

Overall, these findings identify a novel circPLCE1–XYLB–Xu5P metabolic axis governing intestinal fibrogenesis and position fibroblast PPP modulation as a promising antifibrotic therapeutic strategy in Crohn’s disease. The work also expands understanding of how non-coding RNAs regulate stromal cell metabolism and tissue remodeling in chronic intestinal inflammation.