Prim-O-glucosylcimifugin attenuates intestinal fibrosis by modulating TGF-β/MAPK signaling and ECM remodeling

Intestinal fibrosis is a severe and progressive complication of inflammatory bowel disease (IBD), particularly Crohn's disease (CD), for which no effective anti-fibrotic therapies currently exist.

This study aimed to investigate the anti-fibrotic efficacy and underlying mechanisms of Prim-O-glucosylcimifugin (POG), a natural chromone derivative, in TGF-β1-stimulated human intestinal fibroblasts.

Fibrosis was modeled in human intestinal fibroblast cell lines (CCD-18Co) and human primary intestinal myofibroblasts (HIMF) using TGF-β1. POG was administered at varying concentrations, and its effects on fibrotic marker expression, MMP1 activity, and cell migration were evaluated using qPCR, western blotting, immunofluorescence, and wound healing assays. Transcriptomic profiling and integrative pathway analysis were used to identify target signaling cascades.

POG significantly attenuated TGF-β-induced myofibroblast activation, reducing α-SMA, fibronectin, collagen I/III, and N-cadherin levels. Mechanistically, POG suppressed both canonical TGF-β/Smad and non-canonical MAPK/ERK signaling and enhanced extracellular matrix (ECM) turnover by upregulating MMP1 while downregulating TIMP1. Transcriptomic analysis corroborated the involvement of ECM remodeling and ERK pathway inhibition. Importantly, POG exhibited no cytotoxicity in intestinal epithelial cells.

POG demonstrates anti-fibrotic potential in intestinal fibroblasts via dual inhibition of the TGF-β/Smad and MAPK/ERK pathways and selective modulation of ECM-degrading enzymes. These findings highlight POG as a promising therapeutic candidate for the treatment of intestinal fibrosis in IBD.