ADAMDEC1 is not a driver of intestinal fibrosis but a marker of the inflammation-stromal niche in Crohn's disease.

Intestinal fibrosis is a severe complication of Crohn's disease (CD). While ADAMDEC1 has been identified as a marker for specific fibroblast subsets, its functional role in fibrogenesis remains unclear. This study aimed to elucidate the pathophysiological significance of ADAMDEC1 in the fibrotic cascade. We employed a multi-modal approach comprising: (1) re-analysis of transcriptomic data from the pediatric RISK cohort; (2) functional assays using human intestinal fibroblasts (CCD-18Co) involving TGF-β stimulation and ADAMDEC1 overexpression; (3) proteomic analysis of secreted factors in CCD-18Co following ADAMDEC1 overexpression; (4) a murine DSS-induced fibrosis model; and (5) immunohistochemical examination of human CD strictures. In the RISK cohort, ADAMDEC1 expression did not correlate with key fibrosis markers (COL1A1, FN1) despite their upregulation in CD cases. In vitro, while TGF-β induced fibroblast activation, it failed to upregulate ADAMDEC1 expression. Conversely, forced overexpression of ADAMDEC1 did not enhance ECM gene expression or protein secretion. Consistent with these findings, ADAMDEC1 was not upregulated in the murine fibrosis model, and ADAMDEC1-positive fibroblasts were rarely detected in a fibrotic region of human CD stricture tissue. ADAMDEC1 is not a direct driver of fibroblast activation or excessive extracellular matrix production. These findings suggest ADAMDEC1 functions as a niche-specific state marker rather than a central mediator of intestinal fibrosis, indicating it is unlikely to be a primary therapeutic target for reversing fibrotic strictures.