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Prim-O-glucosylcimifugin Attenuates TGF-β-Induced Fibrosis via MAPK Pathway Inhibition and ECM Remodeling in Intestinal Fibroblasts

ABSTRACT: 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-β1 (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-β1-induced fibroblast activation, downregulating fibrotic markers (α-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-β/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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297101 | GEO | 2025/05/18

REPOSITORIES: GEO

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Project description:Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

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Prim-O-glucosylcimifugin Attenuates TGF-β-Induced Fibrosis via MAPK Pathway Inhibition and ECM Remodeling in Intestinal Fibroblasts

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