Garlic‐Derived Exosomes Alleviate Intestinal Fibrosis in Crohn's Disease by Modulating PFKFB3 ‐Mediated Metabolic Reprogramming

Crohn's disease (CD), a chronic inflammatory bowel disease, is frequently complicated by intestinal fibrosis, a process driven by extracellular matrix remodeling. Current therapies lack efficacy in controlling or reversing fibrotic progression, underscoring the need for novel treatments. Here, we found that garlic-derived exosomes (GDE) significantly reduced hydroxyproline production and inhibited the expression of fibrosis-related proteins such as COL1A2, COL3A1, and α-SMA in TGF-β1-treated intestinal fibroblasts. Administration of GDE significantly improved the lesions of the muscular mucosa, the colon shortening, and bowel wall thickness, while also decreasing the expression of COL1A2, COL3A1, and α-SMA in the colon tissues of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mice. Meanwhile, GDE significantly attenuated phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) expression in TGF-β1 treated intestinal fibroblasts and colon tissue of TNBS-induced mice. Both Pfkfb3 gene interruption and PFK-015 (a PFKFB3 inhibitor) markedly prevented the role of GDE in the expression of fibrosis-related biomarkers by blocking the glycolysis pathway and triggering metabolic reprogramming in TGF-β-treated intestinal fibroblasts. Furthermore, fibroblast-specific Pfkfb3 deficiency significantly reduced the fibrosis in the colon tissues of TNBS-induced mice. Taken together, this study reveals the anti-fibrotic mechanism of GDE by regulating Pfkfb3 expression to inhibit the metabolic reprogramming of fibroblasts, which is expected to provide new strategies and targets for the treatment of intestinal fibrosis in patients with CD.