Bulk transcriptomic profiling reveal the epithelial-protective role of ITGBL1 during the progression of colitis
Inflammatory bowel disease (IBD) is characterized by progressive epithelial injury, chronic inflammation, and impaired intestinal barrier function. To comprehensively delineate the epithelial alterations and stress-related responses that occur during colitis progression, we investigated the functional role of integrin beta-like 1 (ITGBL1) in intestinal epithelial cells (IECs). Using patient specimens and DSS-induced colitis models, we identified marked upregulation of ITGBL1 in inflamed intestinal tissues. Loss of ITGBL1 resulted in the emergence of ferroptosis-prone epithelial subsets exhibiting elevated ACSL4 expression, lipid peroxidation, mitochondrial shrinkage, and enhanced oxidative stress, all of which were associated with aggravated epithelial damage and worse inflammatory outcomes. We further demonstrated that ITGBL1 deficiency activated the ANGPT2/PI3K-AKT signaling axis in IECs, leading to exaggerated oxidative stress and ferroptosis, accompanied by reduced expression of key tight-junction proteins including E-cadherin, ZO-1, occludin, and claudin-1. These alterations impaired epithelial cohesion and barrier integrity during disease progression. In contrast, supplementation with recombinant ITGBL1 suppressed ANGPT2 expression, mitigated PI3K-AKT hyperactivation, restored mitochondrial structure, alleviated ferroptosis, and improved epithelial barrier function. In conclusion, ITGBL1 serves as a critical regulator of epithelial stress responses and barrier stability during colitis, acting by restraining ANGPT2-mediated PI3K-AKT activation and ferroptotic cell death. These findings highlight a previously unrecognized epithelial-protective mechanism and identify the ITGBL1–ANGPT2 axis as a potential therapeutic target in IBD. Overall design: Bulk transcriptomic profiling from colonic tissue samples of wild-type mice with 3% DSS–induced colitis(WT,n=3)and from ITGBL1-knockout mice with 3% DSS–induced colitis(ITGBL1-KO,n=3).