Lipid-driven metabolic rewiring promotes intestinal fibrosis in Crohn's disease

Although intestinal fibrosis in Crohn’s disease (CD) has long been attributed to chronic inflammation, emerging evidence suggests that metabolic reprogramming may drive fibrotic progression. The rising incidence of fibrostenotic CD associated with dietary westernization further implicates dietary lipids in pathogenesis, although the underlying mechanisms remain unclear and anti-fibrotic therapies are lacking.Chronic lipid stimulation in CD-derived fibroblasts increased pro-fibrotic genes, proliferation and contractility, together with impaired fatty acid oxidation associated with reduced PPAR-α and L-carnitine levels. Despite compensatory CPT1A upregulation, lipid-treated fibroblasts displayed mitochondrial dysfunction characterized by impaired respiration, mitochondrial swelling, reduced NFE2L2, and increased CALR expression, consistent with oxidative and endoplasmic reticulum stress, without significant activation of NF-κB or interleukin-6 signaling. Integrative spatial and untargeted metabolomics analyses on fibrotic ileum, CD plasma, and lipid-treated fibroblasts, identified extensive lipidome remodeling characterized by reduced phosphatidylcholine (PCs) and accumulation of lysophosphatidylcholines and specific PC species enriched in highly unsaturated ether-linked lipids. Consistently, PC-based liposomes accumulated in the perinuclear compartment and directly induced pro-fibrotic gene expression in fibroblasts. In-vivo, high-fat diet aggravated intestinal strictures and collagen deposition in SAMP1/YitFc mice, recapitulating the metabolic alterations observed in patients.Together, these findings identify lipid-driven metabolic rewiring and mitochondrial dysfunction as central mechanisms promoting intestinal fibrosis independently of classical inflammatory signaling, and highlight restoration of lipid homeostasis as a potential therapeutic strategy for fibrostenotic CD.