Prim-O-glucosylcimifugin Attenuates TGF-ß-Induced Fibrosis via MAPK Pathway Inhibition and ECM Remodeling in Intestinal Fibroblasts
Background: Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), particularly Crohn's disease, and often necessitates surgical intervention due to stricture formation. Despite progress in anti-inflammatory therapies, effective anti-fibrotic treatments remain lacking. Objective: This study evaluated the anti-fibrotic potential and underlying mechanisms of Prim-O-glucosylcimifugin (POG), a natural chromone derivative, in human intestinal fibroblasts. Methods: Fibrosis was induced in human intestinal fibroblast cell lines and primary fibroblasts by TGF-ß1 (2 ng/mL). Cells were treated with POG, and fibrotic marker expression was assessed by immunofluorescence, qPCR, and Western blot. MMP1 activity and fibroblast migration were analyzed. Transcriptomic and integrative network analyses were performed to elucidate molecular mechanisms. Results: POG significantly suppressed TGF-ß1-induced fibroblast activation, downregulating fibrotic markers (a-SMA, fibronectin, collagen I/III, N-cadherin) and inhibiting Smad and MAPK signaling. POG also promoted ECM degradation by upregulating MMP1 and suppressing TIMP1. Transcriptomic data confirmed regulation of pathways involved in ECM remodeling and MAPK signaling. POG displayed no cytotoxicity in intestinal epithelial cells.  Conclusion: POG mitigates intestinal fibrosis by dual inhibition of TGF-ß/Smad and MAPK pathways and by enhancing ECM degradation through selective modulation of the MMP1-TIMP1 axis. These findings support POG as a promising therapeutic candidate for intestinal fibrosis in IBD. Overall design: Comparative gene expression profiling analysis of RNA-seq data for CCD-18co cells by TGF-ß and TGF-ß+POG 30uM