CXCL14 Accelerates Fibroblast Ferroptosis in Inflammatory Bowel Disease by Regulating Lipid Metabolism via SCD1

Abstract

Abstract Inflammatory bowel disease (IBD), historically subdivided into Crohn’s disease and ulcerative colitis, is a chronic, relapsing and heterogeneous condition, resulting in intestinal tissue destruction and dysfunction, such as fibrosis. Currently, there is no effective therapy against colon fibrosis. Fibroblasts are known to contribute to the pathogenesis of IBD-related fibrosis. Recently, our laboratory found that inflammatory fibroblasts in IBD had significantly upregulated Chemokine (C-X-C motif) ligand 14 (CXCL14) expression, suggesting a potential role of CXCL14 in IBD-related fibrosis. Employing Dextran sodium sulfate(DSS)-induced chronic colitis, we showed that CXCL14 was specifically upregulated in collagen-secreting fibroblasts in fibrotic mouse colons. In addition, we showed that CXCL14 was upregulated in human colon fibroblast (HIF and CCD18) culture supernatants induced by transforming growth factor-β1 (TGF-β1), whereas CXCL14 overexpression was sufficient to promote colon fibroblast ferroptosis. Mechanistically, we showed that CXCL14, transcriptionally decreasing the transcript abundance of stearoyl-CoA desaturase-1 (SCD1), mediated its pro-ferroptosis effects by enforcing ERK signaling activity and inhibiting p70 KDa ribosomal protein S6 kinase (S6K) activation in colon fibroblasts. Using a S100 calcium binding protein A4 (S100a4)-cre mice, we generated an intestinal fibroblast-specific CXCL14 knockout mouse line through Adeno-associated virus vectors (AAV) injection into the tail veins. We demonstrated that deletion of CXCL14 in colon fibroblasts accelerated the progression of established colon fibrosis in dextran sodium sulfate (DSS)-induced colitis, suggesting the therapeutic potential of CXCL14 targeting for colon fibrosis and IBD.