LRMDA promotes intestinal mucosal barrier integrity and limits colitis and colon cancer.

Intestinal homeostasis relies on the integrity of the mucosal barrier, whose disruption contributes to inflammatory bowel disease (IBD), enteric infection, and colorectal cancer (CRC). Here, we report that leucine-rich melanocyte differentiation-associated protein (LRMDA) is markedly downregulated in inflamed mucosal tissues from patients with IBD and in colorectal tumor tissues. Genetic ablation of LRMDA in mice exacerbates dextran sulfate sodium (DSS)-induced colitis, enhances colorectal tumorigenesis in both azoxymethane (AOM)/DSS and AOM/Vil-Cre;Trp53 fl/fl models, and increases susceptibility to enteric pathogen infection. LRMDA deficiency is associated with impaired mucin-related gene expression, reduced mucus layer thickness, and compromised intestinal barrier integrity. Ultrastructural analyses further suggest that LRMDA may support mucin granule transport and secretion in goblet cells. Collectively, these findings identify LRMDA as a previously unrecognized contributor to intestinal mucosal barrier integrity and intestinal homeostasis under inflammatory and tumorigenic conditions.